TW200530202A - Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes - Google Patents

Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Description

200530202 IX. Description of the invention: [Technical field to which the invention belongs] (Training 12: Guan compound '# is an inhibitor of dipeptidyl peptidase ~ enzyme (: inhibitor, ...) and can be used to treat or prevent which involves two "Peptidylase" diseases, such as diabetes and especially type 2 diabetes. The present invention also relates to a pharmaceutical composition of a 4 temple compound and these compounds and the combination thereof, which involves a dipeptidyl peptidase-IV enzyme [Previous technology] Cup is related to the disease process derived from multiple causative factors and is characterized by the appearance of glucose or glucose tolerance in oral glucose tolerance test: elevated glucose or glucose Disease. Persistent or uncontrolled ^ and premature incidence and mortality. Frequent abnormal glucose: and indirectly related to changes in lipid, lipoprotein, and apolipoprotein metabolism, other metabolic and hemodynamic diseases. Therefore Patients with type 2 diabetes are particularly at increased risk for megavascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, high 4, kidney disease, neurological disease, and lying membrane disease. Therefore, the therapeutic control of glucose, stability, metabolism, and hyperemia is particularly important in clinical management and diabetes treatment. There are two general cognitive types of diabetes. Type 1 diabetes or insulin-dependent diabetes mellitus (DM) Few or no insulin islets can regulate glucose utilization hormones. In type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM), patients often have the same or even elevated plasma adenine levels, However, these patients have developed resistance to the insulin-stimulating effects of glucose and lipid f metabolism in the main 91662.doc 200530202 sensitive tissues (which are muscle, liver, and adipose tissue) and are elevated The amount of plasma insulin is not sufficient to overcome this significant insulin resistance. Water insulin resistance is not primarily due to a reduced number of insulin receptors but to post-adenin receptor binding defects, which is not known at this time. This is responsive to tenanthin Resistance leads to insufficient insulin activation of glucose uptake, oxidation and storage in muscle and breakdown of lipids in tissue and production of glucose in liver And improper expression of secreted insulin. For many years, the treatments available for virtually unchanged type 2 diabetes have been recognized as limited. Although physical exercise and reduced dietary calorie intake will dramatically improve the condition of diabetes, the treatment of Very poor compliance because = fully infringes on the original lifestyle and excessive food consumption, especially foods with high saturated fat content. Borrowed to continue to use urea (such as tobutazone, buta and e) and Glebe Fasting (glipizide) or megtinide (can lightly stimulate pancreatic β-cells to secrete more insulin) and / or increase the plasma insulin amount by injecting insulin when continuum urea or megtinide becomes ineffective, can Causes Tensin concentrations to be high enough to stimulate each of these insulin-resistant tissues. In the autumn, dangerously low levels of blood polydextrose may result from the administration of insulin or Tendo: ), And an increase in insulin resistance may occur due to even higher amounts of insulin. Increased sensitivity of the bi-pulse class led to some corrections of hyperglycemia. However, the two biguanides, phenformin and melfamin (Symbol formin), can induce lactic acid breakdown and d-zone vomiting / disease. Mefamin has fewer side effects than fenfamin and is often prescribed for the treatment of type 2 diabetes. 91662.doc 200530202 Gitazone (also known as 5-benzyloxazole bite-2,4-dione) is a potential compound that has been more recently described as relieving many of the symptoms of type 2 diabetes. These agents consistently increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, leading to partial or complete correction of elevated plasma glucose without hypoglycemia. Zitazon, currently on the market, is an agonist of peroxisome proliferator-activated receptors (PPARs), mainly of the ρρΑΙι_γ isoform. PPAR-γ subtype agonism is generally believed to be responsible for the improved insulin sensitization observed by Zitazon. Newer ^ PAR agonists that have been tested to treat π diabetes are α, γ, or § subtypes or a combination of these, and in many cases are chemically different from zetazon (i.e., not thiazolidine One'). Some zitas such as trāglitazone have severe side effects. Other methods of treating the disease are still being studied. New biochemical approaches that have recently been introduced or are still under development include treatment with 0C-glycosidase inhibitors (such as acarbose) and protein tyrosine phosphatase_1B (ρτρ_1B) inhibitors. Compounds that are inhibitors of dipeptidyl peptidase-IV ("DP-IV" or "DPP-IV") enzymes are also being investigated as drugs that can be used to treat diabetes, and especially type 2 diabetes. See, for example, WO97 / 4〇832, WO98 / 19998, US Patent No. 5,939,560, Newsletter of Bio-Organic Medicine Chemistry, 6: 1163-1166 (1996) and Newsletter of Bio-Organic Medicine Chemistry, 6: 2745-2748 (1996) . The utility of DP-IV inhibitors in the treatment of type 2 diabetes is based on the fact that DP-IV rapidly deactivates glucagon-like peptide (WGum) and gastric inhibitory peptide (GIp) in vivo. Gu ^, 91662.doc 200530202 and GIP are insulinotropic and are produced when food is consumed. The enterotrophin stimulates insulin production. The inhibitory effect of DP-IV leads to a deactivation of insulinotropin, and this subsequently leads to an increase in the efficiency of insulinotropin in stimulating insulin production by the pancreas. DP_IV inhibition therefore leads to an increase in serum insulin. Advantageously, since intestinal insulinotropic hormones are produced by the human body only when food is consumed, the DP-IV inhibitory effect may increase insulin levels at inappropriate times such as between meals, which may cause excessively low blood glucose (hypoglycemia) . The inhibitory effect of Dpiv is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with insulin secretagogue. DP-IV inhibitors also have other therapeutic utility, as described herein. DP-IV suppression has not been extensively studied so far, especially its utility beyond diabetes. New compounds are needed and it is possible to find improved Dp_IV inhibitors for the treatment of diabetes and potentially other diseases and conditions. The therapeutic potential of coffee preparations in the treatment of type 2 diabetes has been determined by D.j.

Invest. Drugs, 12: 87-100 (2003) ^ ^ K. Augustyns f A ^ Exp.

Opin. Ther. Patents, 13: 499_51〇 (2003). [Summary of the Invention]-The present invention is related to the inhibitor of dipeptidyl peptidase_IV enzyme ("Dp_iv inhibitor ") and can be used to treat or prevent diseases in which dipeptidyl peptidase_IV enzyme is involved. Is a compound of type 2 diabetes). The present invention also relates to the use of pharmaceutical compositions including these compounds and the use of these compounds and compositions for the prevention or treatment of this disease involving the dipeptidyl peptidase_IV enzyme. The present invention Related can be used as: Peptidyl peptidase_IV hexahydro J yamphenein compound. The compound of the present invention is described by the structural formula I: 91662.doc 200530202

Or a pharmaceutically acceptable salt thereof; wherein each n is independently 0, 1 or 2,

Ar is phenyl substituted with 1 to 5 R3 substituents; R is selected from the group consisting of: hydrogen;

Cm. An alkyl group is unsubstituted or unsubstituted, and is independently selected from halide, mesityl group, Cl-6 alkyloxy group, retarder group, Ci-6 alkyloxy group and phenyl-C! · 3 alkoxy (CH2) n aryl, in which the aryl group is unsubstituted or substituted by 5 to 5 independently selected from halogen, CN, hydroxyl, R2 or or, NHS〇2R2, nr2s〇2r2, S02R, Co2H, and Cu alkoxy groups; (CH2) n-heteroaryl, wherein the heteroaryl group is unsubstituted or至 to 3 substituents independently selected from the group consisting of hydroxy, i 素, Cw alkyl and Cl-6 alkoxy, wherein the alkyl and alkoxy are unsubstituted or substituted with 5 to 5 halogens; (CH2) n- Heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with three to three substituents independently selected from the group consisting of oxo, hydroxy, hydrogen, Cw alkyl, and Ci · 6 alkoxy, wherein the alkyl and alkyl The oxy group is unsubstituted or substituted with 5 to 5 halogens; 91662.doc -10- 200530202 (CH ^ -C3 · 6 ring alkyl group wherein the ring group is unsubstituted or is independently selected from 3 to 3 Substituted by 'Wherein the radical and the alkoxy group are unsubstituted or substituted with 5 to 5 halogens; and any methylene (CH2) carbon atom in R is unsubstituted or substituted with 1 to 2 independently selected from halogen, hydroxyl and Unsubstituted or substituted with a substituent of 5 to 5 Cw alkyl groups; each R3 is independently selected from the group consisting of: hydrogen; halogen; cyano; hydroxyl; C 1-6 alkyl, CV6 Alkoxy carboxyl group: unsubstituted or substituted with 1 to 5 i primes; unsubstituted bismuth or substituted with 1 to 5 i primes; alkoxycarbonyl; amino; NHR2; NR2R2; NHS02R2; NR2S02R2; NHCOR2; NR2COR2; NHC02R2; 91662.doc 200530202 nr2co2r2; S02R2; so2nh2; S02NHR2; and so2nr2r2; each R is independently a C! _6 alkyl group, which is unsubstituted or substituted by a substituent independently selected from halogen and alkoxyoxy Substitution; R4 and R5 are independently selected from the group consisting of: · hydrogen; monocyano;

Cw alkoxycarbonyl; alkyl, which is unsubstituted or substituted by 5 to 5 substituents independently selected from halide, _, Cw alkoxy, fluorenyl, Ci_6 alkoxycarbonyl, and phenylalkyloxy Substituted, wherein the alkoxy group is unsubstituted or substituted by: to 5 halogens; (CH2) n-square group. Wherein, the aryl group is unsubstituted or independently selected from the group consisting of halide, meridian, Alkyl and Cl-6 alkoxy are substituted by substituents, in which alkyl and alkoxy are unsubstituted or through 5 to (™ 2) η-heteroaryl 'where heteroaryl is unsubstituted or substituted One independently selected from the group consisting of a substituent of a base, a halogen, a "C" group, and a "c" alkoxy group, wherein the alkyl group and the alkyl group are unsubstituted or substituted with ⑴; Heterocyclyl group is not substituted, please only 91662.doc -12- 200530202 Substituted by substituents of oxo, hydroxyl, halogen, Cw alkyl and Cl K6 ethoxy group, the alkyl group and alkoxy group are not Substituted or substituted by halogen; (CH ^ -Cw cyclohexyl 'wherein the cycloalkyl group is unsubstituted or substituted with 1 to 3 independently selected from halogen, thymyl, Cwhyl and Cl_6 alkoxy Wherein the alkyl group and alkyloxy group are unsubstituted or substituted with halogen; (CHACON ^ 7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, tetrazolyl, thienyldi (CH2) n-phenyl, and (CH2Wf The radicals of the group consisting of an alkyl group and a Ci6 alkyl group are in which the cyano group is unsubstituted or substituted with 5 to 5 halogens and the phenyl and cycloalkyl groups are unsubstituted or substituted with 5 to 5 independently selected from halide, Jingji Cl-6 alkyl and C "6 alkoxy substituents substituted" wherein the alkyl and alkoxy groups are unsubstituted or substituted with a halogen element; or where hR7 and the nitrogen atom to which it is bonded form- A heterocyclic ring of abutidine, pyrrolidine, piperidine, piperidine, and morpholine; and wherein the heterocyclic ring is unsubstituted or independently selected from the group consisting of hydrogen, hydroxyl, and; and, 9 ㈣ and Cl4 oxygen substituents are substituted 'wherein the alkynyl and alkoxy groups are unsubstituted or substituted with 1 to 5 halides; and in which any methylene in R4 or R5 = h2) carbon atoms are unsubstituted or Through a substituent independently selected from the group consisting of a halide, a C1_4 alkyl group substituted with 1 to 5 halogens, each is independently hydrogen or Cl magnetic. In a specific example of the compound of the present invention, the carbon atom marked with * has R configuration as shown in formula Ia 91662.doc -13- 200530202:

Wherein Ar, R1, and R4 are compounds of the present invention. Group: hydrogen; and R9 are as defined herein. In the second specific example, R3 is selected from the group consisting of halogen; cyano;

Cl · 6 alkyl, unsubstituted or substituted with 1 to 5-primes;

Cl-6 alkyllactyl 'is unsubstituted or substituted with 1 to 5 halogens. In this specific example, R3 wrote a group consisting of the Baishan corpse K series, free hydrogen, fluorine, gas, bromine, trifluoromethyl, and methyl. Twice and identify ^ In the specific example of the National People's Congress, R3 is selected from the group consisting of hydrogen, fluorine and chlorine. In the third specific example of the compound of the present invention, w T R is selected from the group consisting of: chlorine; 1 to 5 independently selected from halogen alkoxycarbonyl and benzene

Ci_6 alkynyl 'wherein the alkynyl group is unsubstituted or substituted, hydroxy, Ci-6 alkoxy, carboxyl, c where alkoxy is unsubstituted-substituted by a substituent of Cu alkoxy or substituted by 1 to 5 Halogen substitution; 91662.doc -14- 200530202 (CHA-C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by 1 to 3 independently selected from the group consisting of halo, light, Cl.6 and Ci ^ Oxy substituents, wherein the alkynyl and alkynyl groups are unsubstituted or substituted with a halogen; and any of its methylene groups 2) the carbon atom is unsubstituted or independently selected from halogen , Hydroxyl, and unsubstituted or substituted with 1 Wang: M solid halogen

Cw alkyl is substituted with a substituent. In such specific examples of the compounds of the present invention, R 1 捭 is slowly white. It is "a group of hydrogen consisting of: c 1 _ 4 alkyl groups; 2,2,2-trifluoroethyl; methoxycarbonylmethyl; carboxymethyl Hydroxyethyl; benzyloxymethyl; benzyloxyethyl; and cyclopropyl. In the specific examples of the compounds of the present invention, the group consisting of dibutyl and cyclopropyl is the fourth specific example of the compounds of the present invention. The group of ... hydrogen; R is selected from the group consisting of hydrogen R4 and R5 are selected from the group consisting of lower fluorenyl and the first column, which are unsubstituted or fluorinated to 5 independent k-halides, hydroxyl 91662.doc- 15-200530202, Cw alkyllactyl, carboxyl, Ci-6 alkoxycarbonyl and phenylalkoxy substituents, in which the alkoxy group is unsubstituted or substituted with: to 5 halogens; (2) n aryl , Wherein the aryl group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, Cw alkyl and Cl_6 alkoxy, wherein the alkynyl and alkoxy are unsubstituted or substituted with dentin; (CH2) n-heteroaryl 'wherein the heteroaryl group is unsubstituted or substituted by a; a substituent independently selected from the group consisting of a group, a phenyl group, and a Ci6 alkoxy group; The oxy group is unsubstituted or substituted with 5 to 5 halides; (CH2) n-heterocyclyl, wherein the heterocyclic group is unsubstituted or substituted with 1 to 2 independently selected from oxo, Cl_6 aryl and Ci6 oxo substituted by substituents, in which the alkynyl and oxo are unsubstituted or substituted with two halogens; (CH2) n-C3_6 cyclohexyl 'where cyclinyl is unsubstituted or丨 to 3 substituents independently selected from halogen, hydroxy, Cw alkyl, and Ci 0 alkoxy, wherein the alkyl and alkoxy are unsubstituted or substituted by 丨 to 5; wherein R4 or R5 Any of the fluorenylene (CH2) carbon atoms in this group is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halons, cyclines, and Ci_4 alkyl groups which are unsubstituted or substituted with 1 to 5 carbon atoms. In such specific examples of the compounds of the invention, 'R4 and R5 are independently selected from the group consisting of Dinglie:

91662.doc -16- 200530202

Cu alkyl, which is not substituted with 1 to 5 independently selected from the group consisting of halogen, 土, C " oxo, alkoxy, c, hydroxy, and phenyl-dialkyloxy, Wherein the aryloxy group is unsubstituted or substituted with 5 halogens; (2) n-square group 'wherein the square group is unsubstituted or substituted with i to 5 independently selected from halogen, thiol, alkynyl and Ci-6 Substituted by oxo substituents, which are unsubstituted or substituted with alkoxy, or (CH2) n-heteroaryl, in which heteroaryl is unsubstituted or independently selected from ", i, Cd, and Ci_6 ^ substituents are substituted 'wherein the alkyl group and alkyloxy group are unsubstituted or substituted with a dioxin; (CHA-C3-6 cycloalkyl, where cycloalkyl is unsubstituted Or substituted by three to three substituents independently selected from the group consisting of iin, hydroxy, Cl-6 alkyl, and Ci6 alkoxy, wherein the alkyl and alkoxy groups are unsubstituted or substituted with halogen; where R4 or R5 Any fluorenylene (CH2) carbon atom is unsubstituted or substituted with one to two independently selected from the group consisting of halogen, sulfonyl, and unsubstituted or Cw alkyl substituted with 1 to 5 carbon atoms. The present invention Compound times In specific examples, R4 and R5 are independently selected from the group consisting of: nitrogen; ch3; CH2CH3; CH2CH (CH3) 2; 91662.doc -17- 200530202 CH2-cyclopropyl; CH2-cyclohexyl; CH2OCH2Ph; CH2OH; CH2Ph; CH2 (3-OCF3-Ph); CH2 (4-OCF3-Ph); CH2 (3-CF3,5-CF3-Ph); CH2 (2-CF3-Ph); CH2 (2-Cl- Ph); CH2 (2-Me-Ph); CH2 (2-Me? 5-Me-Ph); CH2 (2-Ph-Ph); CH2 (2-F, 5-F-Ph); CH2 (2 -F-Ph); CH2 (2-F? 3-F-Ph); CH2 (2-pyridyl); CH2 (3-arimidinyl); CH2 (4-arimidinyl); CH2 (1-oxyl Ionic pyridin-2-yl); CH2 (1-oxopyridin-3-yl); CH2 (1H-. Pyrazol-1-yl); CH2 (2-F, 6-F-Ph); and CH2CF3. 91662.doc -18 200530202 In another class of such specific examples, R5 is hydrogen. In a fifth specific example of compounds of the present invention, R8 and R9 are independently selected from hydrogen and methyl. In such specific examples, R8 and R9 is hydrogen. The sixth specific example of the present invention is a compound of formula la, wherein R1 is selected from the group consisting of: 氲; C 1 _ 4 alkyl group; 2, 2, 2-digas ethyl group, methoxycarbonyl group Methyl; carbonylmethyl; hydroxyethyl; benzyloxymethyl; benzyloxyethyl And cyclopropyl; R3 is argon, chlorine or fluorine; R4 is selected from the group consisting of: hydrogen; CH3; CH2CH3; CH2CH (CH3) 2; ch2-cyclopropyl; ch2-cyclohexyl; CH2OCH2Ph; 91662.doc -19- 200530202 ch2oh; CH2Ph; CH2 (3-OCF3-Ph); CH2 (4-OCF3-Ph); and CH2 (3-CF3? 5-CF3-Ph); CH2 (2-CF3-Ph ); CH2 (2-Cl-Ph); CH2 (2-Me-Ph); CH2 (2-Me, _5_Me-Ph); CH2 (2-Ph-Ph); CH2 (2-F, 5-F- Ph); CH2 (2-F-Ph); CH2 (2-F, 3-F-Ph); CH2 (2-pyridyl); CH2 (3-pyridyl); CH2 (4-pyridyl); CH2 (1-oxopyridin-2-yl); CH2 (1-oxopyridin-3-yl); CH2 (1H-oxazol-1-yl); CH2 (2-F, 6-F-Ph) And CH2CF3; and R8 and R9 are hydrogen. In another specific example of this class, R5 is hydrogen. Examples of compounds of the present invention that can be used as dipeptidyl peptidase-IV (but not limited to 91662.doc -20-200530202) are as follows:

-21-91662.doc 200530202

91662.doc -22- 200530202 or a pharmaceutically acceptable salt thereof. As used herein, the following definitions may apply. "Alkyl" and other radicals having the prefix "alkane" such as alkoxy and alkanoyl means a carbon chain which may be straight or branched and combinations thereof, unless the carbon chain is otherwise defined. Examples of radicals Contains methyl, ethyl, propyl, isopropyl, butyl, first and second butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc. When allowed: a specific number of carbon atoms, For example, from C31G, the term Hyunyl also includes% alkyl, and a combination of a straight or branched alkyl chain and a cycloalkyl structure. When the number of carbon atoms is not specified, c16 is intended. &Quot; Cycloalkyl " is a secondary group of alkyl groups and means a group having a specific number of carbon atoms, and a carbocyclic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,% hexyl,% heptyl, ring Octyl, etc. Cycloalkyl is usually monocyclic unless otherwise alkynyl. Cycloalkyl is saturated, unless otherwise defined. Named alkoxy represents a specific number of carbon atoms (such as alkoxy) or any within this range. Straight-chain or branched alkoxides with a number of 1 [ie, methoxy (MeO-), ethoxy'isopropoxy, etc.]. The name "butanethio" represents a specific number of carbon atoms (such as Ci6 alkylthio) or any number of linear or branched alkyl sulfides [i.e. methylthio (MeS-), ethylthio, isopropylthio, etc.) within this range. `` Named amine group '' represents a specific number of carbon atoms (such as alkylamino groups) or any number in this range of linear or branched alkylamines [ie fluorenylamino, ethylamino, isopropylamino, tertiary Butylamino, etc.]. Noun, 'burn-in base' refers to a specific number of carbon atoms (such as Ci_6 alkylsulfonyl) or any number of linear or branched alkyl radicals within this range [ie sulfenyl 91662.doc 200530202 醯(MeS02_), ethyl continuous, isopropylsulfonyl, etc.]. The term "Hexoxy", represents a specific number of carbon atoms (such as Ci4 oxygen), or any number of the invention within this range The linear or branched bond of the slow acid derivative is intended to be [ie, f-based oxoyl (MeOCO_), ethoxy or butyloxy, etc.]. "'Aryl" means a mono- or polycyclic aromatic ring system containing a ring carbon. Preferred aromatics are monocyclic or bicyclic "0-membered aromatic ring systems." Phenyl and naphthyl are preferred: phenyl. The most preferred aryl is phenyl. "Heteroframe" and "heterocyclyl" represent a saturated or unsaturated, non-aromatic ring or% system containing at least one heteroatom selected from 0, 8 and N and further containing sulfur 5 oxidation states such as so and so2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 4 diyin, morphine, K two health, ㈣, ㈣, U • dioxolane, spitting bite, _ sialin, chow, lin Bite, tetrahydroroan, dihydro n-pyran, oxythiocyclopentane, dithiocyclopentane, dioxane, dithiane, thiothiazine, thiomorphine, etc. '' Heteroaryl " means an aromatic or partial square heterocyclic ring containing at least one ring heteroatom selected from 0, S & N. Therefore heteroaryl includes fused to other kinds of rings such as aryl, cycloalkyl and non-aromatic Heteroaryl groups of heterocycles. Examples of heteroaryl groups include: · Isothiazolyl, isothiazolyl, σ-pyazolyl, π-pyridyl ', triazole, oxadiazolyl, thiadiazolyl , Thiazolyl, imidazolyl, triazolyl, tetrazolyl 2, furanyl, trisynyl, thienyl, pyrimidinyl, benzoisoxazolyl, ^ isothiazyl, benzofluorenyl, benzo嗟 disialyl, dihydrobenzo Uranyl,, indololinyl, dacrotyl, carbazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, fluorinyl, phthaloyl, quinazolinyl, naphthyridinyl , Carbazolyl, benzodioxolyl, quinolinyl, purinyl, furyl, isobenzofuro 91662.doc -24 · 200530202 sulfanyl, benzimidyl, benzoyl , Benzopyrene, oxalyl, tenoryl, isorhenyl, dibenzopyranyl, etc. For heteropyrene, 'including rings and ring systems containing from 3.15 atoms' is formed ^ The "ring element" represents fluorine, chlorine, chlorine and fluorine-generally better. When halides are substituted in alkynyl or alkoxy, fluorine is the best (such as CF3acf3ch20). The compounds of the present invention may contain-or more asymmetric intermediates and therefore may be racemates and racemic mixtures, mono-enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the invention have 7 asymmetries on the carbon atoms of the formula lat labeled *. There may be other so-called centers, depending on the nature of each substituent on the molecule. Each such asymmetric center would be within the scope of the present invention to independently produce two optical isomers and it is expected that all possible optical isomers and diastereomers of the mixture and pure or partially purified compounds. The invention is intended to cover all such compounds in this form. Some of the compounds described herein contain olefinic double bonds and are meant to include both E and Z geometric isomers unless otherwise stated. Some of the compounds described herein may exist as tautomers with different hydrogen bonding junctions accompanied by the movement of one or more double bonds. For example, ketones and their enol states are keto-enol tautomers. Individual tautomers and mixtures thereof are included in the compounds of the invention. Formula I shows the structure of such compounds without the preferred stereochemistry. Formula ^ shows the preferred stereochemistry on the carbon atom to which the amino group of the β amino acid is attached in the compounds prepared. The independent synthesis of these diastereomers or its chromatographic separation can be achieved by those skilled in the art by appropriate modification of the methods described herein. Its absolute 91662.doc -25- 200530202 stereochemistry can be based on the lingering, and people hunting right to contain a crystalline product derived from the known reagents of absolute stomach ㈣, or "Ran Zhong ~." X-ray crystallization method If necessary, the racemic mixture of the compound such as the machine "J ,,, and the knife is separated, so that individual enantiomers are isolated. The separation can be carried out by the methods known as "agricultural daggers", such as coupling racemic mixtures of characters to the enantiomeric " isomer mixtures, and then injecting ten, soil 丄 'into the diastereomers of the individual non Enantiomers. This coupling reaction often uses an enantiomeric = acid or shape test ρ. The diastereomeric derivative can then be converted to a pure pair by breaking the added palm residues Enantiomers. The racemic mixture of the compound can also be directly separated from the palm stationary phase by using a 4 m ^ acetone chromatography method, which is a method known in the art. Or 'any of the compound Enantiomers can be obtained using optically pure starting from: or known configurations by selective synthesis methods known in the art. It will be understood that, as described herein, the compounds of formula I are meant to further comprise The pesticide-acceptable salt also includes a precursor when used as a free compound: its pharmaceutically acceptable salt or a salt that is not pharmaceutically acceptable in other synthetic operations. The compound of the present invention can be administered in a pharmaceutically acceptable salt state. Noun, medically acceptable "Salts" represent 2 salts prepared from pharmaceutically acceptable non-toxic bases or acids, which include inorganic or organic bases and inorganic or organic acids. The salts of basic compounds included in the term "pharmaceutically acceptable salts" represent non-toxic salts of the compounds of the present invention, which are prepared by reacting a free base with a suitable organic or inorganic 91662.doc -26- 200530202 acid . Representative salts of the basic compound of the present invention include (but are not limited to) the following: acetate, benzenesulfonate, phenylsulfonate, sulfonium carbonate, argon sulfate, hydrogen tartrate, borate, bromide, camphor Sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate , Esylate, fumarate, glucoheptanoate, gluconate, ammonium, glycolyllarsanilate, hexyl resorcinate , Hydroxylamine salt, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, Maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate salt, naphthalene sulfonate, nitrate, N-fluorenyl gluconate Salt, oleate, oxalate, embonate, palmitate, pantothenate, phosphate Acid salt, polygalacturonic acid salt, salicylic acid salt, stearic acid salt, sulfate, hypoacetic acid salt, succinate salt, tannate salt, tartrate salt, teoletate, toluene Sulfonates, triethiodide and valerates. Furthermore, when the compound of the present invention bears an acidic group, its suitable pharmaceutically acceptable salt includes (but is not limited to) derived from an inorganic test compound, such as inscription, pressing, fishing, copper, iron, ferrous, meridian, town, fierce , Ya Meng _ sodium, the salt of the dictionary. Particularly preferred are ammonium, ca., magnesium, bell and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins such as spermine, betaine, caffeine, choline, N, N_: benzyl ethylenediamine, diethylamine, diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N_ 91662.doc -27- 200530202 ethylmaline, N-ethyl Piperidine, glucosamine, aminoglucoside, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, malein, piperidine, polyamine resin, procaine, purine , Theobromine, diethylamine, trimethylamine, tripropylamine, aminobutanetriol and other salts. Moreover, in the case where a carboxylic acid (-c00h) or an alcohol group is present in the compound of the present invention, a pharmaceutically acceptable ester of a carboxylic acid derivative such as methyl ester, ethyl ester, or monomethylacetoxymethyl Derivatives of esters or alcohols, such as acetate or maleate. Included in this art are the esters and fluorenyl groups that are used to improve the solubility or hydrolysis characteristics of sustained release or prodrug formulations. Solvates, especially hydrates, of compounds of formula I are also included in the present invention. x exemplifies the use of the invention as examples and compounds disclosed herein. The compound can be used for a method for inhibiting mammalian inhibitory substances which need to inhibit the dipeptidyl peptidase_IV enzyme, including administering an effective amount of the compound. Use of the agent. I show a long class like human

——... Α Μ 深 深 mammals. For example, treatable mammals include (but private, feline, dentate, or murine species. However, the method can also be manipulated in species such as bird species (such as chickens). The present invention also relates to manufacturing for use in humans and animals A pharmaceutical method for inhibiting the activity of a dipeptidyl peptidase-V enzyme in the method 'comprises mixing the compound of the present invention with a therapeutically sensible carrier or diluent. $ 91662.doc -28-200530202 Individuals treated in this method- It is generally mammalian and more female), and it needs to inhibit dipeptidyl peptidase, sex or beer i V enzyme activity. The terms "," and "two effective amounts" mean the biological or medicinal response of the compound to the dissolution of tissues, animals, or humans (which is sought by researchers, veterinarians, medical experts, or other clinicians) ) Amount. Q 1 As used herein, the term "composition" is intended to include a product that includes a specific amount of a particular ingredient and any product that results directly or indirectly from a combination of ingredients. This term in relation to a pharmaceutical composition is intended to include products that include active ingredients and the inert ingredients that make up the formula 1 and any products that are derived directly or indirectly from any two: Dissociation of multiple components, or products derived from-or other types of reactions or interactions of multiple components. Accordingly, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention and a pharmaceutically acceptable carrier. " Medicine acceptability " means that the carrier, diluent or excipient needs to be compatible with the other ingredients of the formulation and not adversely affect its prescription. The term "administration" means that the compound should be understood to mean that the compound of the present invention or a prodrug of the compound of the present invention is provided to the individual in need of treatment. The utility of the compound of the present invention as an inhibitor of dipeptidyl peptidase _ v enzyme activity can be borrowed The technique is known to prove. The inhibition constant is determined as follows. Continuous fluorescence analysis is performed with the substrate Gly-Pro_AMC, which releases the fluorescent AMC leaving group by Dp_iv cleavage. The kinetic parameters describing this reaction are as follows: Km = 50 μM keat = 75 f1; keat / Km = L5xl06 JvfV1. A typical reaction contains approximately 50 μL enzyme, 50 μM Gly-Pro-AMC, and a buffer solution (100 mM HEPES, pH 7 5, 0.1 Ag / Zhaisheng 68) The total reaction volume is 100 microliters. The 96-hole disk fluorometer 91662.doc -29- 200530202 was used to continuously track AMC release using an excitation wavelength of 360 nm and an emission wavelength of 46 nm. Under these conditions, approximately 0.8 μM AMC was produced in more than 30 minutes at 25 ° C. The enzymes used in these studies were soluble in the baculovirus expression system (Bac-To-Bac, Gibco BRL) (Except for transmembrane region and cytoplasmic extension) Human proteins. Hydrolyzed by Gly-Pro-AMC and GLP-1 The kinetic constant was found to be consistent with the natural enzyme value in the literature. In order to measure the dissociation constant of the compound, a solution of an inhibitor in DMS 0 was added to the reaction containing the enzyme and the substrate (final DMSO concentration 1%). All experiments used the above standard The reaction conditions are performed at room temperature. In order to determine the dissociation constant (Ki), the reaction rate is incorporated into the Michaelis-Menton program for competition suppression by nonlinear regression. The error of the dissociation constant is typically less than 2 times. In particular, the following The activity of the solid compound in inhibiting dibasic enzyme-IV enzymes in the above analysis is generally 1 (: less than about 1 μM. This result is the inherent activity of the compound used as an inhibitor of dipeptidyl peptidase-IV enzyme activity. The index of dipeptidyl peptidase_IV enzyme (DP_IV) is a cell surface protein associated with a wide range of biological functions. It has a wide tissue distribution (intestine, kidney, liver,

Pancreas, placenta, thymus, spleen, epidermal cells, vascular endothelial cells, lymph and spinal cord cells, serum) and different tissue and cell type expressions. DP_IV is a modulator of T cell activation marker gene CD26, an endocrine and neurological peptide. It can cleave several kinds of immunity in vitro. It has been suggested that this peptidase can play a potential role in the development of various diseases in humans or other species. 91662.doc -30- 200530202 Type II diabetes and related diseases. Insulin-stimulating insulin glp_i and Gjp have been fully established in vivo by DP-IV. The study of uranium and bed uranium in deficient mice showed that DP-IV inhibition increased the steady-state concentration (^^-丨 and out?), Resulting in improved glucose tolerance. Similar to GLP-1 and GIP, the same Other glucagon family peptides involved in glucose regulation are also deactivated by DP-IV (such as PACAP). Deactivation of these peptides by dp_IV2 also plays an important role in glucose and other stability. Therefore, the DP- IV inhibitors are useful in the treatment of type 2 diabetes and in the treatment and prevention of several conditions often associated with type 2 diabetes ^, which include the syndrome χ (also known as the metabolic syndrome), reactive hypoglycemia, and Diabetic dyslipidemia. The following obesity is another condition often associated with type 11 diabetes that can be treated with the compounds of the invention. The following diseases, disorders and conditions are related to type 2 diabetes and can therefore be treated with the compounds of the invention Be treated, controlled, or prevented in some cases: (1) 咼 glycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) Dyslipidemia (7) Hyperlipidemia, ("Hyperglycemia," (9) Hypercholesterolemia, (10) Low HDL, 0J) High LDL, (12) Arteriosclerosis and its secondary disease , (13) blood vessel reocclusion, (14) irritating bowel syndrome, (15) inflammatory bowel disease including Cologne's disease and colon ulcers, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity Disease, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) symptom group X, (24) hyperovarian androgen (polycystic ovarian syndrome) and Among them, insulin resistance is another factor of a factor. In the syndrome χ (also known as the metabolic syndrome), obesity is considered to promote insulin resistance, obesity 91662.doc 200530202, dyslipidemia, hypertension And increased cardiovascular disease. Therefore, DP-IV inhibitors can also be used to treat hypertension associated with this condition. Obesity: DP-IV can be used to treat obesity. This is based on food intake and GLP-1 and GLP Inhibitory effect observed on gastric emptying of -2. Externally administered GLP-1 in humans Reduce food intake and gastric emptying (Am · J. Physiol ·, 277: R910-R916 (1999)). GLP-1 administration to mice and mice via ICV also has a significant effect on food intake (Nature Medicine, 2: 1254-125 8 (1996)). The inhibitory effect of this diet was not seen in glP-IR mice, and these effects were regulated by the brain GLP-1 receptor. Similar to GLP-1 ' GLP-2 is also regulated by DP-IV. The administration of icv to GLP-2 also inhibits food intake 'similar to the effect observed with GLP_1 (Nature

Medicine, 6: 802-807 (2000)). In addition, studies with dp-IV deficient mice suggest that these animals are resistant to diet-induced obesity and related pathologies such as hyperinsulinemia. Growth hormone deficiency: DP-IV inhibitory effect can be used to treat growth hormone deficiency, based on the theory that growth hormone release factor (GRF) (a type that stimulates the release of growth hormone from the anterior pituitary gland) uses DP-iv in the body. Enzyme breaks (W0 00/5 6297). The following data provide evidence that GRf is an endogenous substrate: (l) GRF effectively breaks in vitro to produce an inactive product grf [3_44] (BBA 1 122: 147-153 (1992)); (2) GRF is in plasma Rapid degradation to GRF [3_44] 'This can be prevented by the DP-IV inhibitor diproutin A; and (3) GRF [3-44] found in the plasma of human GRF transgenic pigs (J · Clin · Invest · '83 = 1533-1540). Therefore DP-IV inhibitors can be used for the same indications as growth hormone secretagogues. 91662.doc _ 32 · 200530202 Intestinal injury: The potential for the use of DP-IV inhibitors for the treatment of intestinal injury is demonstrated by glucagon-like peptide-2 (GLP-2) (a similar endogenous species of DP-IV (Substances) The results of studies on the nutritional effects of intestinal epidermal cells are known (Regulatory Peptides, 90: 27-32 (2000)). Administration of GLP-2 results in increased intestinal mass in rodents and weakens intestinal damage in rodent models of colitis and enteritis. Immunosuppressive agents: DP-IV can be used to regulate the immune response. It is based on the study of the effects of DP-IV enzymes on T-I packet activation and the effects of DP-IV inhibitors in the process of chemical activin and in living models of diseases. DP " " IV has been shown to be the same as CD26, a cell surface marker gene that activates immune cells. The performance of CD26 is regulated by the differentiation and activation status of immune cells. It is generally accepted that CD26 functions as a co-stimulator in an in vitro model of T cell activation. Several cytokines contain proline in a secondary position, presumably to protect them from degradation by non-specific aminopeptidases. Many of these have been shown to be processed in vitro by DP-IV. In several cases (RANTES, LD78-PMDC, eotaxin, SDF-la), fragmentation leads to altered activity in chemical chemotaxis and signaling analysis. Receptor selectivity also seems to be modified in some cases (RANTES). Multiple N-terminally deactivated ends of several chemoactivins have been identified in in vitro cell culture systems, including predicted products of DP-IV hydrolysis. DP-IV inhibitors have been shown to be effective immunosuppressive agents in animal models of transplantation and arthritis. Prodipine (Pro-Pro-diphenyl-fillerate), a reversible inhibitor of DP-IV, has shown double heart allograft survival in mice from 7 to 14 days (Transplantation, 63: 1495-1500 (1997)). DP-IV inhibitors have been tested in collagen and alkyldiamine-induced arthritis in mice 91662.doc -33- 200530202 and have shown statistically significant weakening of hind paw swelling in this model [Int. J. Immunopharmacology 19: 15-24 (1997) A Immunopharmacology, 40: 21-26 (1998)]. DP-IV is up-regulated in several autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Graves' disease, and Hashimoto's thyroiditis. HIV infection: DP-IV inhibitory effects can be used to treat or prevent HIV infection or AIDS, as several chemical activins that inhibit HIV cell entry are potential host substances for DP-IV (Immunology Today 20: 367-375 (1999)) . In the case of SDF-1α, cleavage reduces antiviral activity (PANS, 95: 633 1-6 (1998)). Therefore, the stabilizing effect of SDF-1α by inhibiting DP-IV would be expected to reduce HIV infectivity. Hematopoietic: DP-IV inhibition can be used to treat or prevent hematopoiesis, as DP_IV may involve hematopoiesis. DP-IV inhibitor Val-Boro-Pro stimulates hematopoiesis in a mouse model of cyclophosphamide-induced neutropenia (WO 99/56753) ° Neuronal disorders: DP-IV inhibition can be used for treatment or Prevention of various neuronal or psychiatric disorders, as several peptides related to various neuronal processes are broken by DP-IV in vitro. Therefore inhibitors can have therapeutic benefits in the treatment of neuronal disorders. Endomorphine_2, β-casomorphin, and substance P are shown to be in vitro recipients of DP-IV. In all cases, the in vitro rupture was highly effective, with a keat / Km of about 106 M "S_1. The DP-IV inhibitor showed a significant effect in the electric shock jumping test in a mouse model of no pain, and it was not related to the presence of exogenous endomorphine-2. (Brain Research, 815: 278-286 (1999)). The neuroprotective and nerve regeneration effects of DP-IV inhibitors can also be protected by the inhibitor 91662.doc -34- 200530202, the ability to protect motor neurons from stimulating toxin cell death, The ability to protect the striated nerve distribution of dopaminergic neurons when co-administered with MPτρ, and the ability to promote the recovery of striated nerve distribution density when administered therapeutically after MPTP treatment [see Yong-Q · Wu et al., "Neuroprotective effects of dipeptidyl peptidase-IV inhibitors in vitro and in vivo", Int. Conf. Αι

Dipetidyl Aminopeptidase: Basic Science and Clinical Application, September 26-29, 2002 (Berlin, Germany)]. Tumor invasion and migration: DP-IV inhibitory effects can be used to treat or prevent tumor invasion and migration, as several isopeptidases containing DP-IV have been observed to increase or decrease during normal cell transformation into a malignant phenotype (J. Exp Mec ^ 190: 301-305 (1999)). The regulation of these proteins up or down appears to be specific to tissues and cell types. For example, increased CD26 / DP-IV manifestations have been observed in D-cell lymphoma, T-cell acute lymphoblastic lymphoma, cell-derived thymoma, basal cell carcinoma, and breast cancer. Therefore, DP-IV inhibitors have utility in the treatment of these cancers. Benign Prostatic Hypertrophy: DP-IV inhibition can be used to treat benign prostatic hypertrophy, as increased DP-IV activity has been found in prostate tissue from patients with BPH (Eur · J · Clin. Chem. Clin · Biochem ·, 30: 333-338 (1992)). Sperm mobility / male contraception: DP-IV inhibition can be used to alter sperm mobility and be used for male contraception because of the high levels of semen, prostate bodies, and small prostate-derived organs that are important for sperm mobility DP-IV activity (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)). Gingivitis: DP_IV inhibition can be used to treat gingivitis, because DP-IV activity is found in the gingival crevicular fluid and in some studies has been associated with the severity of periodontal disease 91662.doc -35- 200530202 (Arch. Oral · Biol · 37: 167-173 (1992)). Osteoporosis · DP-IV inhibition can be used to treat or prevent osteoporosis because the GIP receptor is present in osteoblasts. Bong invention compounds in

'A Drink Shainiu T has utilization: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia , (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, 〇) low volume, (11) high LDL volume, (12) arteriosclerosis and its secondary disease , (13) Re-occlusion of blood vessels, (14) Irritable bowel syndrome, (15) Inflammatory bowel diseases including Cologne's disease and colonic cancer, (16) Other inflammatory conditions, (17) Pancreatitis, ... German obesity Disease, (19) neurodegenerative disease, (20) retinopathy, (2ι) nephropathy, (22) neuropathy, (23) symptom group χ, (hypergrowth androgen (polycystic Indian nest syndrome) , (25) type diabetes, ⑽ growth hormone deficiency, 中 neutropenia, (28) neuronal disorders, (29) tumor migration, 良 benign prostatic hypertrophy, (32) gingivitis, (33) high Bloodemia and other conditions that can be treated or prevented by inhibiting DP_IV. This compound can be combined with other agents to prevent or treat the aforementioned diseases, J1 premature disorders and diseases In the method, the present compound can be used in combination with one or more other agents to treat, prevent, or alleviate a disease or condition, which is a formula M and has an available disease or condition. Safer or more drunk μ: Chinese medicines are administered together in combination than alone-amount ... = This other medicine can be used in the usual way and with ^ Compounds can be administered simultaneously or sequentially /, and other drugs are used at the same time / Xi Temple A good combination is a pharmaceutical composition of 91662.doc -36- 200530202 unit dosage form containing this other drug and a compound of formula 丨. However, the combination therapy may also include a treatment in which the compound of formula I and one or more drugs are administered in different overlapping courses It is also expected that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients may be used in lower doses than when each is used alone. Accordingly, the pharmaceutical composition of the present invention contains One or more other active ingredients. Examples of other active ingredients that can be administered in combination (either separately or in the same composition) of a compound of formula I include (but are not limited to) · (A) other dipeptidyl peptidase IV (DP-IV) inhibitors; (b) insulin sensitizers include (i) PPARy agonists such as glitazone (such as troglitazone, Pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and other PPAR ligands include ppARa / γ dual agonists such as KRP-297 and PPARa agonists such as Aromatic acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate); (ii) Biguanides such as US and France Metformin and phenformin; and (iii) protein tyrosine phosphatase_1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylurea and other insulins Secretins such as tolbutamide, glybmide, glipizide, glimepiride, and megiitinide such as repaglinide ); (E) a-glucosidase inhibitors (such as acarose (acar | 30se) and miglitol); 91662.doc -37- 200530202 (f) pancreatic height Glucagon receptor antagonists as described in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810; (g) GLP-1, GLP-1 mimetics and GLP-1 receptor agonists As described in WO 00/42026 and WO 00/59887; (h) GIP and GIP mimetics as described in WO 00/58360 and GIP receptor agonists; (i) PACAP, PACAP mimetics and PACAP receptor agonists Agents are as described in WO 01/23420; (j) Cholesterol-lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin ), Cerivastatin, fluvastatin, atovastatin, itavastatin and rosuvastatin, rosuvastatin, and other statins Class); (ii) sequestering agents (such as cholestyramine, corestipol and cross-linked dextran dialkylamine derivatives); (iii) nicotinamide, nicotine Acids or salts thereof; (iv) PPARa agonists such as aryloxybenzoic acid derivatives (gemfibrozil, clofibrate, fenofibrate, and bechafi Bezafibrate); (v) PPARa / γ dual agonists such as KRP-297; (vi) Cholesterol absorption inhibitors such as β-glutitol and ezetimibe; (iv) CoA: cholesterol Acid transferase inhibitors such as avasimibe; and (viii) antioxidants such as probucol; (k) PPAR5 agonists as described in WO 97/28149; (l) anti-obesity compounds Such as fenfluramine, dexfenfluraminee, phentermine, sibutramine, orlistat, neuropeptide Y5 or Y5 antagonist, 91662. doc -38- 200530202 CB-1 receptor inverse agonist and antagonist, β3 adrenergic receptor agonist, melanocortin receptor agonist, especially melanin · 4 receptor agonist, ghrelin antagonist And melanin-concentrating hormone (MCH) receptor antagonists; (m) ileal bile acid transmission inhibitors; (η) agents for inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, aphids (Azulfidine) and selective cyclooxygenase-2 inhibitors; (〇) antihypertensive agents such as ACE inhibitors (innarin enalapril), lisinopril, captopril, qUinapril, tandolapril), A-II receptor blockers (losartan, losartan, Candesartan, irbesartan, valsartan, telmisartan, eprosartan), beta blockers and calcium channel blockers ; And (P) glucokinase activators (GKAs). Dipeptidyl peptidase IV inhibitors that can be administered to the compounds of formula I of the present invention include those described in WO 03/004498 (January 16, 2003); WO 03/004496 (January 16, 2003); EP1 25 & 476 (November 20, 2002); WO 02/083128 (October 24, 2002); WO 02/062764 (August 15, 2002); WO 03/000250 (January 3, 2003); WO 03/002530 (January 9, 2003); WO 03/002531 (January 9, 2003); WO 03/002553 (January 9, 2003); WO 03/002593 (January 9, 2003) ); WO 03/000180 (January 3, 2003); and WO 03/000181 (January 3, 2003). Specific DP-IV inhibitor compounds include thiazolium isoleucine; NVP-DPP728; P32 / 98; P93 / 01; and LAF237. Anti-obesity compounds that can be combined with compounds of structural formula I include phenfluoro 91662.doc -39- 200530202 amine, phenflumine, phentermine, hibutamine, oreste, neuropeptide! Or Y5 antagonist Agent, cannabis CB-1 receptor antagonist or inverse agonist, melatonin receptor agonist, especially melatonin-4 receptor agonist, ghrelin antagonist and melanin concentration hormone (MCH) Receptor antagonist. An overview of anti-obesity compounds that can be combined with compounds of structural formula I can be found in S. Chaki et al., `` Recent Advances in Eating Inhibitors: Therapeutic Strategies π Before Treatment of Obesity, Expert Opin. Ther · Patents, 11: 1677-1692 ( 2001) and D. Spanswick and K. Lee, fl Germinated anti-obesity drugs π, Expert Opin. Emerging Drugs, 8: 217-237 (2003). Neuropeptide Y5 antagonists that can combine compounds of Structural Formula I include those described in US Patent No. 6,335,3 45 (January 1, 2002) and WO 01/14376 (March 1, 2001); and referred to as GW 598 84A; GW 5 69180A; LY 366377; and CGP-71683A specific compounds. Cannabinoid CB 1 receptor cumin inhibitors that can be combined with compounds of structural formula I include those described in WO 03/007887; U.S. Patent No. 5,624,941 as issued by Rimonabant; PCT Publication No.WO 02/076949 as SLV-319; US Patent No. 6,028,084; PCT Publication No. WO 98/41519; PCT Publication No. WO 00/10968; PCT Publication No. WO 99/02499; US Patent No. 5,532,237; and US Patent No. 5,292,736. Melatonin receptor agonists that can be combined with compounds of formula I include those described in WO 03/009847 (February 6, 2003); WO 02/068388 (September 6, 2002); WO 99/64002 (1999 December 16, 2014); WO 00/74679 (December 14, 2000); WO 01/70708 (September 27, 2001); and WO 01/7033 7 (September 27, 2001) and disclosures In JD Speake et al., 91662.doc -40- 200530202 Recent progress in the development of melatonin-4 receptor agonists ", Expert 〇pin. Ther.

Patents, 12: 1631-1638 (2002). The potential availability of safe and effective activators of glucokinase (GKAs) for the treatment of diabetes is discussed in J. Grimsby et al., Allosteric activation of glucokinase 糖尿病 Potential role in diabetes / Taiwan therapy, Science, ⑽ 乃 ⑼. The above combinations include not only the combination of the compound of the present invention and other active compounds, but also the combination with two or more active compounds. Non-limiting examples include a compound of formula I and two or more selected from the group consisting of biguanide, sulfonylurea, HMG-CgA reductase inhibitor, PPAR agonist, 叩 -⑺ inhibitor, ..., other DP IV inhibitors and anti- A combination of active compounds in a group of obese compounds. Similarly, the compound of the present invention can be used in combination with other drugs that can be used to treat / prevent / suppress or relieve the diseases or conditions available for the compound. This other medicine can be administered by its usual route and amount, and it can be administered at the same time or in sequence with ^ month chemical σ. When a compound of the present invention is associated with—or multiple other pills! Tau uses 4, preferably a pharmaceutical composition containing this other table compound in addition to the compound of the present invention. Accordingly, the pharmaceutical composition of the present invention contains one that contains-or more other active ingredients-in addition to the compound of the present invention. The weight ratio of the present moisturizer to the second active ingredient may vary and will depend on the effective dose of the oral ingredient. An effective dose of each ingredient is usually used. Because when the compound of the present invention is combined with other drugs, the compound of the present invention will meet the other pharmacological agents. The ratio is about 1000: 1 to about 1: 100, preferably about 200: 1. To about 1 test. The combination of the compound of the present invention and other active ingredients is generally in the front wall, but in each case, an effective dose of 91662.doc -41-200530202 should be used. In this combination, the compound of the present invention is a medicine. In addition, the -element may be administered simultaneously in other dispensable compounds. The compounds of the present invention may be administered orally, simultaneously or sequentially. Intravenous, caffeine, intracranial injection or intramuscular, intraperitoneal, inhalation spray, intranasal, intravaginal two subcutaneous injections-can be formulated alone or-from the beginning, containing conventionally suitable for each route = = and acceptable carrier Adjuvants and tailor-made non-essential facial medicines treat warm-blooded animals such as mice, mice, and horses; In addition to and the like, the compounds of the present invention are effective for use in humans. "The monkey == inventive compound's pharmaceutical composition should be prepared by a method known in the dosage domain. All methods include mixing the pupa, knife, or a carrier of multiple auxiliary ingredients. In general, the ^ compounds are uniform and close The active ingredient is mixed with the liquid carrier or the dibody carrier or both, and then the product is required to be formed into the desired shoulder formulation. In the pharmaceutical composition, the active main compound and the content of the active ingredient are for disease 2 A person whose development or condition is sufficient to produce the desired effect. As used herein, a "composition" is intended to include a product that includes a specific amount of a specific ingredient and any product obtained directly or indirectly from a specific ingredient of group 3 The pharmaceutical composition may be in a dosage form suitable for oral use, such as lozenges, dragees, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or sweeteners. Compositions for oral administration may be prepared according to any known method in the field of manufacturing pharmaceutical compositions and the composition may contain one or more selected from the group consisting of sweeteners, flavoring agents, 91662.doc -42- 20053020 2 Pharmaceuticals in the group of colorants and preservatives have provided medicinal delightful and delicious preparations. Lozenges contain a mixture of active ingredients and non-toxic pharmaceutically acceptable excipients suitable for manufacturing lozenges. These excipients It may be, for example, an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as stearin Magnesium acid, stearic acid or talc. Lozenges may be uncoated or they may be coated by known techniques to prolong disintegration and absorption in the gastrointestinal tract and thereby provide long-term, sustained activity. For example, time delay materials such as Hard moon ^ glyceride or glyceryl distearate. It can also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic keys for controlled release. Oral The formulation used may also be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or a filial pie gelatin capsule in which the active ingredient is in water or oil Such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain a mixture of active ingredients and excipients suitable for use in the manufacture of aqueous suspensions. This excipient is a suspending agent such as sodium carboxymethyl cellulose, methyl fiber Cellulose, hydroxy-propyl cellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth, and gum arabic; dispersants or wetting agents may be natural phospholipids such as sealant or condensation products of alkylene oxides with fatty acids such as polyoxygen Condensation products of ethylene stearate or ethylene glycol and long-chain aliphatic alcohols, such as seventeen ethoxylated green wax alcohols, or ethylene oxide and 4 derived from fatty acids and hexitols are S condensation products such as polyoxyethylene sorbitol monooleate, or the condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, 91662.doc 200530202 such as polyethylene glycol sorbitol drunk Anhydrous early oil I know. The aqueous suspension may also contain one or more preservatives such as p-butylene: F, benzene, fg, ethyl acetate or n-propyl ester, one or more coloring ingredients, one 5 ^^^ / evening flavoring agent, and one or more Sweeteners such as sucrose or sugar. The formulation of the oil suspension allows the active ingredient to be suspended in a vegetable oil such as flower oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid stone. The oily suspension may contain a thickening agent such as osmium, hard rock, or alcohol. Sweeteners and flavoring agents as described above can be added to provide a pleasant mouth. The composition can be preserved by adding an antioxidant such as ascorbic acid. ', Dispersible powders and granules suitable for preparing an aqueous dispersion by adding water are provided as the active ingredient in a mixture with a dispersant or a wetting agent, a suspending agent, and / or a plurality of preservatives. Examples of suitable dispersing and wetting suspending agents are as described above. Other excipients may also be present, such as sweeteners, bitters and colorants. The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil or a mineral oil such as liquid paraffin or a mixture of the temple. Suitable emulsifiers can be natural gums such as gum arabic or tragacanth, natural fats such as soybeans, butter fat, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and the same Condensation products with oxyethane such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and sweeteners can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. This formulation may also contain humectants, preservatives, and flavoring agents. 91662.doc -44- 200530202 colorants. The pharmaceutical composition can form +

， 十 十 奴 囷 can inject water-based or oily counties, Mou this L sweat can be used in accordance with this technique Xinxin liquid. This suspenseful method uses the above mentioned hope, Yih emollients and suspending agents. Find suitable and for Powder or injectable preparations can also be intestinal acceptable diluted, non-free, non-liquid, such as sterilized injectable solutions or suspension solvents in water, such as water, forest Grignard, ~~ solution. The acceptable carrier can be used and 0-and isotonic sodium chloride solution. In addition, Xi used the right to fix the oil as A, and six as 1 I know as Mixtures or suspension media. For this purpose, any brand of fixed oils containing human, a, crease fatty acids such as oil i found σ or-glycidol. In addition, it is used in injectable preparations. The compounds of the present invention can also be Suppository forms can be administered transrectally to 5 substances, which can be prepared by mixing the drug with solid at normal temperature but in the rectum :: sound group 4 and meltable in the rectum to explain that the intestine M is liquid. Therefore, this substance; Sexual excipients mix bevon cocoa butter and polyethylene glycol. Say 'can use the compounds containing the present invention *, freeze-depleted, solutions or suspensions (Ri phase, I human τ, containing mouthwash and mouthwash). Α For the purpose of' local application should include complex compounds and methods and Includes other active compounds described herein that are generally used in the treatment of the above-mentioned conditions. Treatment or prevention of conditions that require inhibition of A-^^ J-like basal enzyme-IV enzyme activity, About 0.01 to 500 mg / kg as soon as one or more doses are administered. Compared to ancient / eight dagger, about 0.1 to about 250 mg Λ kg / day, more preferably about 0.5 to about 100 mg / Kg / day is about 0.01 to 250 mg / kg / day II and β to 100 g / kg / day in the back, 91662.doc -45- 200530202 or about 0.1 to about 50 mg / kg / total, 5 n Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg & " Fine Entry Wheel > 丄 Brown A catty / day. For oral administration, the, And, it is better to improve the dosage form of tablets containing active ingredients from 0 to 15 milligrams. 〇, 15G.G, 2_, 25G.G, _.g, 4_, 5ggg, 6〇 ^ 800, 800 · 0, 9〇〇〇 and looo.o Bitter thumb & active ingredients, see the adjustment of the symptoms of the disease you want to treat. The compound can be administered once a day, preferably once or twice a day on the mother's day. When used to treat or prevent diabetes and / or hyperglycemia Or homotrioleic acid oleateemia or other diseases to which the compound of the present invention can adapt, when the compound of the present invention is administered at a dose of about 0.1 mg to about 100 mg / kg of animal body weight, a satisfactory result is obtained. It can be administered in a single daily dose or twice daily to eight people's scalpels, or in a sustained release dosage form. For most classes, the total dose is from about 1.0 mg to about 1000 mg, preferably from about 1 gram to about 50 ¾. In the case of a 70 kg adult, the total daily dose is usually about 7¾ grams to about 350¾ grams. This dose course can be judged to provide the most therapeutic response. ^. It is necessary to understand that the specific amount and number of administrations for any particular patient will be variable and will depend on several factors, including the activity of the compound used, the metabolic stability and duration of action of the compound, age, general health, gender, Nuliang, nucleus and time of medicine, secretion rate, drug combination, severity of specific condition, and host undergoing treatment. Several methods for preparing the compounds of the present invention are illustrated in the following reaction schemes and examples. The starting materials are prepared according to procedures known in the art or as described herein. 91662.doc -46- 200530202 The compound of the present invention can be obtained from a β amino acid intermediate as shown in Formula II and a substituted hexahydrodiπaheptane_ intermediate as shown in Formula III using standard peptide coupling conditions followed by Deprotected and prepared. The preparation of these intermediates is described in the following reaction Figure 0

Π III where Ar, R1, -R4, R5, R8 and R9 are as defined above and ρ is a suitable nitrogen protecting group such as a third butoxyl (BOC), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxy Ficoc. Reaction circle 1 NH Ar

1) / BuOCOCI, Et3N 2) CH2N2

II 103) PhC02Ag Compounds of formula II are commercially available, known in the literature, or can be prepared by various methods known in the art. A general path is illustrated in Figure 1. Protected U-amino acids which are commercially available or easy to use such as di-tertiary butyl dicarbonate (for P = BOC), carbonylbenzyloxychloride (for p = cbz) or ^ ( ^ Fluorenylmethoxycarbonyloxy) succinimine (for P = Fmoc). Prepared from the corresponding amino acid by protection) and react with isobutyl chloroformate and triethylamine or N, N-diisopropylethylamine, followed by reaction with diazomethane. The resulting diazonium g is then treated with silver benzoate in a solvent such as methanol or aqueous dioxane, and can be sonicated according to the procedure of Sewald et al., Synthesis, 837 (1997) according to 91662.doc -47- 200530202. Provides beta amino acid II. As will be understood by those skilled in the art, for the preparation of enantiomerically pure β amino acid II, enantiomerically pure α amino acid 1 may be used. Another route for protected β-amino acid intermediates II can be found in the following overview: E. Juaristi, enantioselective synthesis of β-amino acids, edited by Wiley-VCH, New York: 1997; Juaristi et al., Aldrichimica Acta, 27: 3 (1994); and Cole et al., Tetrahedron, 32: 9517 (1994). Reaction circle 2 h2n

HC1 2 C02Me. +

1) NaOH / H2O, 70oC 2) 0 (CO〇tBu) 2

N ^ .C02Me

Boc 4

Boc

0〇2Μθ LiOH THF / MeOH n ^ c ^ co2h

H2, Pt〇2

CHC13, EtOH

The NH 6 dioxane or TFA / CH2CI2 compound of formula III can be obtained commercially, is known in the literature, or can be prepared by various methods known in the art. One convenient method in which R1 is hydrogen is shown in Reaction Scheme 2. Amino ester 2 (preferably using its hydrochloride) is condensed with acrylonitrile i and the amine group of the formed product is protected as, for example, its third butoxycarbonyl (Boc) derivative, and 4,91662.doc -48-200530202 is obtained. Reduction to primary amine 5.5. Cyclization to N-protected hexahydrodiheptain-7 can be performed using dimethylaluminum. Alternatively, amino ester 5 can be hydrolyzed to acid 6 and cyclized using an amino acid coupling reagent such as EDC to obtain intermediate 7. In the example of Boc, the intermediate Ilia is obtained by deprotection by treatment with an acid such as hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane. Reaction 囷 3

1. Benzotriazole, SoCI; 2.

NC

NHR1 9 DIPEA, CH2CI2 R4

inb

Pt02, CHCI3

Another method for preparing hexahydrodiazepinone IIIb (where R5, R8, and R9 are hydrogen) by EtOH, H2 is shown in Reaction Scheme 3. Keto acids and pyruvates can be identified by aminopropionitrile to obtain hydroethyl oxofluorenol, which can be reductively cyclized to hexahydrodiazepinone IIIb by reducing agents such as oxidation and nitrogen. Reaction circle 4

NH R5

_1.NaH.DMF 2.R1I or F ^ Br

91662.doc -49 200530202

or TFA / CH2CI

R5> ^ Hexachlorodiheptanone m and its intermediates can be modified in various ways. For example, the ammonium nitrogen of intermediate 7 (prepared as shown in Figure 2) can be alkylated by deprotection with a base such as sodium hydride. Then, the ethane-based dentate treatment is shown in the reaction diagram 4. The resulting intermediate 11 is deprotected to obtain intermediate III. Reaction Figure 5

Another example of this is illustrated in Reaction Figure 5. Protected hexahydrodiazepine because of the same 12 (which can be prepared as described in the reaction in Figure 4 R4 and R8 are synthetic intermediates ^ or from the reaction Figure 3 to protect the intermediate nia where R5 is hydrogen and (Preparation) can be alkylated using a base such as LDA followed by treatment with various alkylates. This method can be repeated to introduce a second alkyl group R8. Deprotection to obtain intermediate III. Reaction circle 6

91662.doc -50- 200530202

Ar

To protect

N—R1r5P For example, TFA / CH2CI2 vs. P = Boc 13

N ~ R1 Intermediates II and III are coupled under standard peptide coupling conditions, such as the use of 丨 ethyl-3- (3-dimethylaminopropyl) carbodiimide and 丨 _hydroxybenzotriazole (EDC / HOBT) or 〇- (7_azabenzotriazole-bakib team ^^^-tetramethylurea hexafluorophosphate and 1-hydroxy_7_azabenzotriazole (hatu / 〇at) Coupling in a solvent such as N, N-dimethylamidine (DMF) or dichloromethane at ambient temperature for 3 to 48 hours to obtain intermediate 13, as shown in the reaction of Figure 6. In some cases' Intermediate III may be a salt such as hydrochloride or trigasacetate, and in these examples, N, N--s ^^^, monoisopropylethylamine is added to the coupling reaction. Then, in the example of Boc, the protective group is removed with, for example, diwon ’s death, -methanol, hydrogen chloride, or methanolic hydrogen chloride. The product can be recrystallized, dispersed, preparative thin reed, Rapid chromatography on Shi Xijiao, such as feeding, or alcoholication. The compounds of Dream II :: can be isolated as the corresponding salts. The purification of intermediates is based on the product described in the above reaction diagram in the SI column. Or synthetic intermediates

: Step refinement, such as the operation of substituents on Ar, ~ or R5, and modification of J and other operations can be ordered (for X decoration 丨 F bei. What should I do?) D S (ren is not limited to) this skill knows well And hydrolysis reactions. In some cases, the order of performing the aforementioned reaction diagrams can be changed to speed up the reaction or avoid unwanted reaction products. The following examples are provided to better understand the present Invention. These examples are for illustrative purposes only and should not be used to limit the invention. Intermediate 1

(3R) _3 · [(Third butoxycarbonyl) amino group difluorophenyl) butanoic acid step name A · (i, S) -N_ (third butoxymethylene) -2,5-difluorobenzene To a solution of 0.5 g (2.49 mmol) of 2,5-difluoro_DL_phenylalanine in 5 ml of a second butanol solution, sequentially add 15 ml of a 2N sodium hydroxide aqueous solution and 543 ¾ g of di-third butyl dicarbonate. The reaction was stirred at ambient temperature for 16 hours and diluted with ethyl acetate. The organic phase was sequentially washed with 1N hydrochloric acid and brine, dehydrated with magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 97: 2 "methane: methanol: acetic acid) to obtain the title compound. MS 302 (M + 1) 〇 Step B: (R, s) _3-[(Third-butoxycarbonyl) amino] -1-diazo-4_ (2,5-difluoro-phenyl) but-2 -Ketone in a solution of 2.23 g (7.4 mmol) of (R, S) -N- (third butoxycarbonyl) > 2,5-difluorophenylalanine in 100 ml of ether, in order Add 137 ml (8.1 mol) of triethylamine and 0.931 ml (7.5 mmol) of tert-butyl formic acid and stir the reaction at this temperature for 15 minutes. Then add dichloromethane-cooled ether solution until it remains yellow Stirring was continued for 16 hours. The acid 91662.doc -52- 200530202 was added dropwise to capture diazomethane, and the reaction was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium hydrogen peroxide solution, and brine. Dehydrate with magnesium sulfate and concentrate in vacuo. Diazone is obtained by flash chromatography (silica gel, 4: 丨 hexane: ethyl acetate). LU NMR (500 MHz? CDC13) δ 7.03-6.95 (m? 1Η)? 6.95 -6.88 (m? 2Η)? 5.43 (bs5 1Η), 5.18 (bs, 1Η), 4.45 (bs, 1Η), 3.19-3.12 (m, 1Η), 2.97-2.80 (m, 1Η), 1.38 (s, 9H) Step C: (3R) -3-[(Third butoxycarbonyl) amino] _4_ (2,5_difluoro (R), butyric acid in 2.14 g (6.58 mmol) of (R, S) _3-[(third butoxycarbonyl) amino] 1 squirrel-4 ^ · (2,5-monogas-benzyl ) Butan-2-pyrene dissolved in 100¾ liters of methanol, and 3.3 ml (19 mmol) of diisopropylethylamine and 302 mg (1.32 mmol) of benzoic acid were sequentially added at -30 ° C. Silver. After stirring for 90 minutes, the reaction was diluted with ethyl acetate and washed sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic phase was dehydrated with magnesium sulfate, concentrated in vacuo, and prepared by preparative HPLC (Chiralpak AD tube). Right, 5% ethanol was burned) to separate the enantiomers' to obtain 550 mg of the required (R) -enantiomer, which was first dissolved out. This material was dissolved in 50 ml of tetrahydrofuran: methanol: in hydroxide Lithium aqueous solution mixture (3: 1: 1) and stirred at 50 ° C for 4 hours. The reaction was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine and dehydrated with magnesium sulfate And concentrated in vacuo to obtain the title compound as a white foam solid. W NMR (500 MHz, CDC13) δ 7.21 (m, 1H), 6.98 (m, 2H), 6.10 (bs, 1H), 5.05 (m, 1H), 4.21 (m, 1H), 2.98 (m, 2H), 2.60 (m, 2H), 1.38 (s, 9H) 91662.doc -53- 200530202 Intermediate 2

(3R) -3 _ [(Third butoxycarbonyl) amino] _4- [2_fluoro_4_ (trifluoromethyl) phenyl] Butyric acid Step A: (2R, 5S) _2,5_ dihydro · 3 , 6-Dimethoxy_2- (2, -fluoro-4,-(trifluoromethyl) benzyl) -5-isopropylβ has a commercial taste of 3.32 g (18 mmol) 23) _2,5-Dihydro-3,6-dimethoxy-2-isopropyl η is added to 100 ml of tetrahydrofuran solution at -70 ° C, and 12 ml (19 mmol) is added at -70 ° C. ) Of 1.6M butyl lithium in hexane. After stirring at this temperature for 20 minutes, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20 ml of tetramethylfuran solution was added and stirring was continued for 3 hours, and the reaction temperature was allowed to warm to Ambient temperature. The reaction was quenched with water, concentrated in vacuo and extracted with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexane) gave the title compound. lU NMR (500 MHz, CDC13) δ 7.33-7.25 (m, 3Η) 5 4.35-4.31 (m5 1Η), 3.75 (s5 3H), 3.65 (s, 3H), 3.60 (t, lH, J = 3.4 Hz) , 3.33 (dd, 1H, J = 4.6, 13.5 Hz), 3.03 (dd, 1H, J = 7, 13.5 Hz), 2.25-2.15 (m, 1H), 1.0 (d, 3H, J = 7 Hz ), 0.66 (d, 3H, J = 7 Hz) Step B: (R) -N- (third butoxycarbonyl) -2-fluoro-4-trifluoromethyl-phenylalanine methyl ester 91662.doc -54- 200530202 in 5.5 g (15 mmol) of (2κ, 58) -2,5-dihydro-3,6_dimethoxy-2- (2'-fluoro-4 '-(tri To a solution of 50 ml of acetonitrile · methylene chloride (10: 1) in a mixture of fluoromethyl) benzyl) isopropylσ, 80 ml of a 1N trifluoroacetic acid aqueous solution was added. The reaction was stirred for 6 hours and the organic solvent was removed by vacuuming. Sodium carbonate was added until the solution was basic (> ρ 8). The reaction was then diluted with 100 ml of tetrahydrofuran and 10 g (46¾ mol) of di-tert-butyl dicarbonate was added. The resulting slurry was stirred for 16 hours and vacuumed and extracted with ethyl acetate. The combined organic phases were washed 'with brine, dried and concentrated in vacuo. Purification by flash chromatography (dream gum, 20% ethyl acetate) afforded the title compound. ! H NMR (500 MHz, CDC13) δ 7.38-7.28 (m? 3Η)? 5.10 (bd, 1Η) 5 4.65-3.98 (m, 1Η), 3.76 (s, 3Η), 3.32-3.25 (m, 1Η), 3.13-3.05 (m, 1Η), 1.40 (s, 9Η) Step C ·· (R) -N- (third butoxycarbonyl) -2 · fluoro-4_trifluoromethyl-benzene 5.1g (14 mmol) of (R, S) -N- (third butoxycarbonyl) -2-fluoro-4-trifluoromethyl-phenylalanine methyl ester in 350 ml of tetrahydrofuran : Methanol: in lithium hydroxide (3: 1: 1) mixture was stirred at 50 ° C for 4 hours. The reaction was cooled, acidified with 5% hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound. lH NMR (500 MHz, CD3OD) δ 7.45-7.38 (m? 3H)? 4.44-4.40 (m? 1H) 9 3.38-3.33 (m, 1H), 2.98 (dd, 1H, J = 9.6, 13.5 Hz), 1.44 (s, 9H) Step name D · (3R) -3 _ [(Third butoxyalkyl) amino] _4_ [2-Gas_4_ (trifluoromethyl) phenyl] butyric acid containing 3.4 g ( 9.7 millimolar) of step C in 60 milliliters of tetrahydrofuran solution, at 0 ° C, 2.3 milliliters (13 millimoles) of diisopropylethylamine and 91662.doc -55- 200530202 1.7 milliliters (13 millimoles) Mol) isobutyl chloroformate and the reaction was stirred at this temperature for μ minutes. The cooled diazomethane ether solution was then added until the yellow color continued and stirring was continued for 16 hours. The excess diazocarbamate was captured by the dropwise addition of acetic acid and the reaction was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dehydrated with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 9: 1 hexane: ethyl acetate) gave 0.05 g of diazone. In a solution of 0.5 g (1.3 3 mmol) of diazolone dissolved in 100 μl of methanol, at 0 °. (: Next, add 0.7 ml (4 mmol) of diisopropylethylamine and 32 mg (013 mmol) of silver benzoate in order. After stirring for 2 hours, dilute with ethyl acetate and sequentially with 2 N Wash the strips with hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dehydrated with magnesium sulfate, concentrated in vacuo and dissolved in 50 ml of a mixture of tetrahydrofuran: methanol: in lithium hydroxide aqueous solution (3: 1: 1), and at 5 (: Stirred for 3 hours. The reaction was cooled, acidified with 5% hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dehydrated with magnesium sulfate and concentrated in vacuo to give the title compound as a white foamy solid. lH NMR (500 MHz, CD3OD): δ 7.47-7.33 (m? 3Η)? 4.88 (bs, 1Η), 4.26-3.98 (m, 1H), 3.06-3.01 (m, 1H), 2.83-2.77 (m, 1H), 2.58-2.50 (m, 2H), 1.29 (s, 9H) intermediate 3

91662.doc -56- 200530202 (3R) _3 _ [(Third butoxycarbonyl) amino group] _Heart (2,4,5 · trifluorophenyl) butanecarboxylic acid Step A: (2S, 5R) -2, 5-Dihydro_3,6_dimethoxy-2_isodiyl-S- (2 ', 4,5, -trifluorobenzyl) pyridine from 3.42 g (18.5 mmol) 2S) _2,5-dihydro-3,6-dimethoxy_2_ Isopropylamine and 5 grams (22.3 millimoles) of 2,4,5_trifluorobenzyl bromide 2 The procedure described in step A to prepare the title compound (3.8 μg). lU NMR (500 MHz, CDC13): δ 7.01 (m9 1Η)? 6.85 (m? 1Η)? 4.22 (m? m% 3.78 (m, 3H), 3.64 (m, 3H), 3.61 (m, 1H), 3.20 (m, 1H), 2.98 (m, 1H), 2.20 (m, 1H), 0.99 (d5 3H, J = 8 Hz), 〇62 (d, 3H, J = 8 Hz) Step B : (R) _N- (Third butoxycarbonyl) _2,4,5_trifluorophenylalanine methyl ester (2S, 5R) -2,5-di in 3.81 g (11.6 mmol) Hydrogen-3,6-dimethoxy-2-isopropyl_5- (2'54 ', 5'-trifluorobenzyl) was added to 20 ml of acetonitrile solution, and 20 ml of 2N hydrochloric acid was added. The reaction was stirred 72 hours and concentrated in vacuo. The residue was dissolved in 30 ml of digas methane and 10 ml (72 mmol) of triethylamine and 9.68 g (44.8 mmol) of di-third butyl dicarbonate were added. The reaction was stirred for 16 Hours, diluted with ethyl acetate and washed sequentially with 1N hydrochloric acid and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 9: 1 hexane: ethyl acetate) to obtain the title compound. LU NMR (500 MHz? CDC13): δ 6.99 (m? 1H)? 6.94 (m? 1H) 5 5.08 (m5 1H), 4.58 (m, 1H), 3.78 (m, 3H), 3.19 (m , 1H), 3.01 (m, 1H), L41 (s, 9H) Step C: (R) _N- (third butoxycarbonyl) _2,4,5_trifluorophenylalanine from 2.41 g (7.5 moles) of (R) _N- (Third butoxycarbonyl) _2,4,5-trifluorophenylalanine phosphonium ester was prepared using the procedure described in Intermediate 2 Step C (2.01 g). 91662.doc -57- 200530202 LC-MS 220.9 (M + 1-BOC) 〇 Step D: (3R) _3 _ [(Third butoxycarbonyl) amino group 4- (2,4,5-trifluorophenyl) butyric acid at 0.37 g (1.16 mmol) Mol) of the third butoxycarbonyl group) _2,4,5-trifluorophenylalanine in a 10 ml ether solution at -20. (: Sequentially add 193 liters (1.3 mol) of triethylamine and 0.8 ml (1.3 mmol) of isobutyl chloroformate and the reaction is allowed to cool at this temperature for 15 minutes. Add cooling The diazomethane solution was kept yellow until it continued to stir for another 1 hour. The diazomethane was captured by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with a saturated sodium bicarbonate aqueous solution and brine. It was dehydrated with sulfuric acid and concentrated in vacuo. Purified by flash chromatography (Shi Xijiao, 3: 1 hexane: ethyl acetate) to obtain 0,36 g of diazoketone. In 1,2 Nitrozaki, dissolved in 12 ml : 26 mg (0.113 mmol) of silver benzoate was added to a solution of 0.35 g (1; 15 mmol) of diazopanane in water (5: 1). After the resulting solution was sonicated for 2 hours, acetic acid was added. Diluted with ethyl acetate and washed sequentially with 1 ν hydrochloric acid and brine 'dehydrated with sulfuric acid and concentrated in vacuo. Purified by flash chromatography (second film, 97.2.1 one gas methyl alcohol · methanol · acetic acid) to obtain the title compound. 4 NMR (500 MHz, CDC13) δ 7.06 (m, 1Η), 6.95 (m, 1Η), 5.06 (bs, 1Η), 4.18 (m, 1H), 2.98 (m, 2H) 2.61 (m, 2H), 1.39 (s, 9H) Intermediate 4

91662.doc -58- 200530202 (called 4- (2 · Yen-4, S-difluorophenyl) _3 _ [(Third-butoxyquinyl) amino] butyric acid in 2.4 g (10 mmol) 2 _Bromo_4,5_difluorobenzoic acid [prepared according to the procedure of ㈣a et al., Syn. Comm., 3067 — 3074 (1992)] was added to a solution of tetrahydrofuran in ml, and 2.43 g (15 mmol) of carbonyl di Imidazole. This solution was heated at reflux for 3.5 hours' and cooled to ambient temperature and 15 ml of water containing 0.38 g (10 mmol) of sodium borohydride was added. The reaction was stirred for 10 minutes and partitioned between ethyl acetate and 10% carbonic acid. Between aqueous sodium hydrogen solution. The organic layer was washed twice with warm water and brine, dehydrated with magnesium sulfate, and concentrated in vacuo. Purified by flash chromatography (silica gel, n-hexane: ethyl acetate). 9 g 2_ Bromo_4,5_difluorobenzyl alcohol. In a 30 ml solution of dichloromethane containing g (8.4 mmol) of 2-mo-4,5-difluorobenzyl alcohol, 3.4 g (at 0 ° C) 10 millimoles) of carbon tetrabromide and 27 grams (10 millimoles) of triphenylphosphine. The reaction was stirred at this temperature for 2 hours. The solvent was removed in vacuo and the residue was stirred with 100 ml of ether. , Vacuum concentration and fast Purification by chromatography (silica gel, 20: 1 hexane: ethyl acetate) gave 29 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide, which was used without further purification. Used The procedure described in Preparation of Intermediate 2-4 was used to convert the benzyl bromide derivative to the title compound. LC-MS 394 and 396 (M + 1). Basically following the procedure described in Preparation of Intermediate 1-4, Table 1 was prepared. Intermediate 0

2

OH 91662.doc -59- 200530202 Intermediate R3 Selected 1HNMR data (CD3OD) 5 2-F, 4-Cl, 5-F 7.11 (dd, 1 H, J = 8.9, 6.4 Hz), 7.03 (dd, 1 H, J = 9.0, 6.6) 6 2-F, 5-Cl 7.27 (dd, 1 H, J = 6.4, 2.5 Hz), 7.21 (m. 1 H), 7.03 (U 1 H, J = 9.2 Hz ) 7 2-Me, 5-Cl 7.16 (d, 1 H, J = 1.8 Hz), 7.11-7.07 (m, 2 H), 2.34 (s, 3 H) 8 2-Cl, 5-Cl 7.34 (d , 1 H, J = 9.0), 7.33 (d, 1 H, J = 2.1 Hz), 7.21 (dd, 1 H, J = 8.5, 2.5 Hz) 9 2-F, 3-Cl, 6-F 7.35 ( td, 1 H, J = 8.5, 5.8 Hz), 6.95 (t, 1 H, J = 8.5 Hz) 10 3-Cl, 4-F 7.33 (d, 1 H, J = 6.9 Hz), 7.19-7.11 ( m, 2 H) 11 2-F, 3-F, 6-F 7.18-7.12 (m, 1H), 6.91 (m, 1 H) 12 2-F, 4-F, 6-F 6.81 (t, 2H , J = 8.4Hz) 13 2-OCH2Ph, 5-F 7.49 (d, 2 H, J = 7.6 Hz), 7.38 (t, 2 H, J = 7.3 Hz), 7.3.0 (t, 1 H, J = 7.3 Hz), 6.96-6.89 (m, 3 H), 5.11 (d, 1 H, J = 11.7 Hz), 5.08 (d, lH, J = 11.9 Hz) [Embodiment] Example 1

91662.doc -60- 200530202 (3R) _4 _ [(called 3_amino ice (2,45 triphenyl) butyryl)] hexakis_3methyl-2H-1,4-diphyllene_ 2_ Ketohydrochloride Buma A: N (Third Butoxymethyl) -Nm ethyl) _D_Alanine methyl ester in h Alanine formamidine hydrochloride (2 questions) and 5N aqueous sodium hydroxide solution (2 · 9 ml) of water (15 ml) was stirred into the suspension, and acrylonitrile was added under replacement ... ml). The resulting mixture was at 70. 〇㈣3.5 hours and cooled to room temperature. Di-tertiary butyric acid dicarbonate (30 mL) was added and the reaction mixture was stirred for 2 days. The reaction mixture was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate / hexane 2: 3) to obtain N- (third butoxycarbonyl) cyanoethyl) -D-alanine methyl ester. Step B: N · (3-aminopropyl) _N_ (third butoxycarbonyl) _D-alanine methyl ester at N (first butoxy & yl) _n_ (2-cyanoethyl). _ To a solution of methyl alanine (15 g) in ethanol (80 ml) and chloroform (1.4 ml) was added platinum oxide (350 mg), and the reaction mixture was stirred under hydrogen for 6 hours. The mixture was filtered through celite and the celite was washed with methanol and dichloromethane. The filtrate was concentrated to obtain N- (3-aminopropyl) tert-butoxycarbonyl)-!)-Alanine methyl ester as an oily residue. Step C ·· (2R) -Hydrogen · 2-methyl-3_oxodiazepine third butyl ester in 2M trimethylaluminum dichloromethane solution (3 () ml) slowly add N_ (3-Aminopropyl) -N- (third butoxycarbonyl) alanine methyl ester (^^ g) in dichloromethane. The reaction mixture was stirred at room temperature for 4 days and then poured into a bottle containing 30 grams of Shixi bath soil. The mixture was stirred and quenched by slowly adding about 10 ml of a saturated 91662.doc -61-200530202 aqueous ammonium chloride solution. Add sodium sulfate (20 g * ^ A surname 1 liter (50 ml). Mix. Stir for 1 hour and then filter. The solid is washed with 5% tritium, V, tritium, T% / digas methane. / Residue / night / chen ,,, couple. Residues were obtained by flash chromatography (silica gel, ^ order of 4, 6, 7 and 12% of 10: 1 methanol / concentrated ammonium hydroxide aqueous solution of the second emulsion Tane> Gu Li ) To obtain the title compound containing less than 3% (3S) -isomer. LC / MS 228 · 9 (M + 1). Step D: It is called hexahydro-3_methylamine, 4 diazepine phase The (2R) _hexahydro_2_methyl_3_oxocarbon 1-formic acid obtained in the previous step of the hydrochloride salt, tributyl vinegar was dissolved in 2% of hydrogen chloride and evaporated after 2.5 hours. The hydrochloride salt of the compound. Step name E: (called 4-K3RM-[(third butyloxy) amino group] · 4 (2 4 5 · trifluorophenyl) butylfluorenyl] hexahydro-3-methyl- 2Η_14_Diazepene-2- 嗣 in N-methylmorpholine (0.38 ml) and (3R) _3 _ [(third butoxycarbonyl) amino] -4- (2,4,5-tri To a 20 ml solution of dichloromethane in fluorophenyl) butanoic acid (1.0 g) was added isobutyl chloroformate (0.39 ml) at -20 ° C. The resulting mixture was stirred for 1 hour. $. Add the second one containing (3R) _hexamidine-3 -methyl-2H_1,4_diπyaheptene-2-hydrazone hydrochloride (500¾g) and N-methylmorphine (0.40ml) Chlorine compound (5 ml) and DMF (8 liters). Stir the mixture for 28 hours, initially stir at -20 and then slow it to ambient temperature. The reaction is quenched by the addition of saturated ammonium chloride solution and sequentially Extracted with methane and ethyl acetate. The combined organic layers were washed sequentially with water and brine, dehydrated with sodium sulfate and concentrated. The residue was chromatographed (silica gel, 3% to 7% 10: 1 methanol / concentrated). Coupling product was obtained by purification with ammonium hydroxide in dichloromethane). This was further purified by dissolving the product in a mixture of ethanol (7.5 ml) at 50 ° C 91662.doc -62- 200530202 and hexane (16 ml). The solution was allowed to cool to ambient temperature overnight and then placed in cold; 3 hours in the east cabinet. The solid was collected and washed with cooled 5% ethanol / hexane to obtain the title compound. Step F: (3RM-[(3R) | amine Winter (2,4,5trifluorophenyl) butylfluorenyl] hydrogen-3-methyl-2H-1,4-diazepine-2-one hydrochloride Step E of (3R) _4-[(3R) _3 _ [(Third butoxycarbonyl) amino ] _4_ (2,4,5_

Difluorophenyl) butylammonium] hexahydro-3_methyl ^ 仏 丨 ^ —diazepine_2_one was treated with 4N hydrogenated dioxane, stirred for 2.5 hours and evaporated to obtain the title compound. LC / MS 344.1 (M + 1). Example 2

4-[(3R) -3-amino-4- (2,5 · difluorophenyl) butylfluorenyl] hexahydro] methyl-2Η-1,4-diazepine-2-one hydrochloride step A: N- (3-aminopropyl) -N- (third butoxycarbonyl) glycine methyl ester was prepared from methyl glycine hydrochloride according to the method described in Example AB, Step AB to prepare the title compound. LC / MS 241.0 (M + 1). Step B: Hexahydro_3_oxo_1Η-1,4-diazepine_1β formate third butyl acetate in N- (3-aminopropyl) -N- (third butoxyweiyl) To a solution of methyl glycine vinegar (0.2 g) in tetrahydrofuran (THF) / methanol (2/1, 300 ml) was added a 1 M aqueous solution of benzyl hydroxide (60 ml). The resulting mixture was stirred at room temperature overnight. 2091662.doc -63- 200530202 ml of a 1M aqueous solution of chlorooxidized bell was added and the mixture was stirred for 6 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 50 ml of methanol and 200 ml of toluene and concentrated in vacuo. To the residue was added ethyl_3_ (3_dimethylmethylpropyl) carbodicarbonate in dichloromethane (300 ml) Peryleneimine (EDC, 9.6 g) and __hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at room temperature for 3 days, and then treated with a saturated aqueous solution of chloroform and extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, 1 to 5% methanol / ammonium hydroxide aqueous solution (10: 1) in dichloromethane) to obtain the title compound. LS / MS 215.0 (M + 1). Step C:

Hexahydro-4-methyl-3-oxodiazepine q-tributyl ester

Sodium hydride (103 mg) was added to a stirred solution of DMF (5 ml) in hexahydro-3_oxodioxane-3-butylacetate. After that, iodoxane (0.15 ml) was added, and the resulting mixture was stirred at 0 ° C, or at room temperature overnight. It was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed sequentially with a saturated aqueous sodium bicarbonate solution and brine, dehydrated with sodium sulfate, and concentrated to obtain the product, which was not further purified. Step D: Λ hydrogen small methyl Xie, 4-di-p-heptane_2_fluorene hydrochloride Example 2 Hexahydro_4_methyl_3_oxo · -diazepine 1 obtained in step C -The third butyl formate was dissolved in 4M hydrogen chloride bisphenol and evaporated at 2.5% to obtain the title compound. Step E: 4 _ [(3R) -3 · [(Third butoxycarbonyl) amino group] _4_ (2,5_difluorophenyl) butylfluorenyl] hexahydro-1-methyl-2H-1,4- Diazepine · 2_ 鲖 91662.doc -64- 200530202 (3R) -3-[(Second butoxycarbonyl) amino] _4- (2,5-difluorophenyl) butanoic acid (40 pens G), EDC (29 mg) and HOBT (21 mg) in a stirred mixture of dichloromethane and triethylamine (0.042 ml) and hexahydro "-methyl · 2Η-1,4_two-mouth yahegine-2 -Ketone hydrochloride (33 mg). The resulting mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified by preparative TLC (silica gel, 8% 10: 1 methanol / concentrated ammonium hydroxide in dichloromethane) to obtain the title compound. Step F: / H (3R) -3-amino_4- (2,5-difluorophenyl) butylfluorenyl] hexahydro-1-methyl · 2Η-1,4-di-P-heptane · 2- 4-[(3R) -3-[(Third-butoxycarbonyl) amino group> 4_ (2,5_difluorophenyl) butylfluorenyl] hexahydro-1-methyl-2Η_1,4 obtained from ketone step E -Diazepine-2 -one was treated with 4N hydrogen chloride in dinar roast, stirred for 4 hours and evaporated to obtain the title compound. LC / MS 326.0 (Μ + 1) 〇 Example 3

(3R) -4-[(3R) -3-amino-4- (2,4,5-trifluorophenyl) butylfluorenyl] hexahydro ^ methyl-2, -1,4-diazepine-2 -Ketohydrochloride Step A: Hexahydrogen prepared in Example 2 Step C by 2-benzylhexahydro-4 · methyl · 3-oxo-1H_1,4_diazepine_ι_carboxylic acid third butyl ester _4_ Thyroid oxoheptin-butyric acid tert-butyl vinegar (180 mg) in thF (8 ml) stirred solution, add -78C diisopropylamidamine (LDA) solution (1.5M cyclohexane) , 91662.doc -65- 200530202 0.53 ml). The mixture was stirred for 40 minutes and benzyl bromide (0.28 ml) was added. The resulting mixture was at -781: stirred for 6 hours. The reaction mixture was then diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, 2% methanol / dichloromethane) to obtain the title compound. Step B · 3-benzylhexahydro-1-methyl-2H-1,4-diazepine-2-one hydrochloride 2-benzylhexahydro-4-methyl-3 obtained in step A -Oxo-1H-1,4-diazepine-1-third butyl formate was dissolved in 4M dioxane hydrochloride and evaporated after 2.5 hours to obtain the hydrochloride salt of the desired compound. Step C: (3R) -4-[(3R) -3-[(Third butoxycarbonyl) amino] _4- (2,4,5-trifluorophenyl) butyridyl] -3-benzylhexa Hydrogen_1_methyl-2H-1,4_-p-aheptene-2-嗣 N-methylmorpholine (0.048 ml) and tert-butyl formate (0.026 ml) were added to -2 (TC (3R) -3-[(Third butoxycarbonyl) amino] -4- (2,4,5_trifluorophenyl) butanoic acid (67 mg) in a stirred solution of THF (1 ml), and the resulting mixture Stir for 1 hour. Add 3-benzylhexahydro_ 丨 -methyl-2H-1,4-diazepine.in-2-one hydrochloride (48 mg) and N-methyl obtained in step B? (1 ml) in DMF (0024 ml). The mixture was stirred at 20 ° C for 30 minutes and at ambient temperature for 36 hours, then evaporated. The residue was treated with saturated aqueous ammonium chloride solution and ethyl acetate. It is extracted and the organic extract is evaporated. The obtained product is purified by preparative TLC (silica gel, methanol / concentrated ammonium hydroxide / dichloromethane 4.4: 0 ^: 95.5) to obtain a coupled product of a mixture of diastereomers. This isomer was resolved by HPLC (ChiralPAK AD, 14% ethanol / hexane) and the (R, S) -isomer that dissolves quickly was collected Slowly dissolving (Isobium isomers. 91662.doc -66-200530202 Step D: (3R) -4-[(3R) _3-Amino · 4 · (2,4,5_trifluorophenyl ) Butanyl] _3. Benzylhexahydro-1-methyl-2'-1,4-diazepine_2_one hydrochloride The title compound of Step C was dissolved in 4M hydrogen chloride in dioxane and after 2.5 hours Evaporation gave the desired product. LC / MS 434.1 (M + 1) Example 4

ocf3 (3RM _ [(3R) _3_amino_4_ (2,4,5_trifluorophenyl) butylfluorenyl] hexahydro-3_ [4_ (trifluoromethoxy) benzylazepine 2 因 Step A · 4 · [(benzyloxy) methyl] hexahydro_3_oxodiazepine-1-carboxylic acid tert-butyl acetate from hexahydro-3-oxo-1H-1,4-diazepine_ ; _ The third butyl gallate (Example 2 step B) and the benzyl gas methyl ether were prepared essentially as described in Example 2 step c. Step B: M (benzyloxy) methyl] six Hydrogen_3_oxo_2 [4_ (trigasmethoxy) benzyl] -1Η-1,4-diazepinecarboxylic acid third butyl ester from 4 _ [(benzyloxy) methyl] hexahydro- 3-oxo-1Η-1,4-diazepine j-form " butyl hydrazone and 4- (difluorofluorenyloxy) benzyl bromide followed the procedure in Example 3 to prepare the title compound. ^ Step C · Hexahydro-3-oxo_2- [4- (trifluoromethoxy) benzyl] _iH 14-monoheptene-1_formic acid tert-butyl acetate 91662.doc -67- 200530202 in 4- [(Benzyloxy) methyl] hexahydro-3-oxo-2- [4- (trifluoromethoxy) benzyl] -1Η-1,4-diazepine_1-carboxylic acid third butyl 10% palladium / carbon (300 mg) in a solution of the ester (520 mg) in ethanol (17 ml) The reaction mixture was stirred under hydrogen for 22 hours. A few drops of water were added and stirring was continued for another 20 hours. The mixture was filtered through celite and the diatomaceous earth was washed with ethyl acetate. The filtrate was evaporated under reduced pressure. The residue was evaporated under Biotage (^ g). Purification by chromatography (silica gel, methanol / concentrated ammonium hydroxide aqueous solution / monomethyl chloride 1 · 5: 0: 0: 98 · 4). The resulting product was dissolved in toluene and refluxed for 3 hours. The title compound was obtained by evaporation in vacuo without further development. Purification was used in the next step. Step D ·· Hexahydro · 3- [4- (trifluoromethoxy) benzylb 2H-1,4-diazepine-2-one hydrochloride hexahydro-3 -Oxo-2- [4- (trifluoromethoxy) benzyl] -1] 9 > 1,4-diazepine-1-carboxylic acid third butyl ester is dissolved in 4M hydrogen chloride in dioxane and After 2 · 5 hours, the desired product was obtained by evaporation. Step E ··· (3R) -4 _ [(3R) -3 _ [(Third Butoxycarbonyl) amino] _4_ (24s_difluorophenyl) butylfluorenyl] hexahydro- 3_ [4_ (trifluoromethoxy) benzyl] _2H-1,4-di-p-heptane · 2-ketone N-methylmorpholine (0.072 ml) and third butyl chloroformate (〇 〇39mL) was added to -2 (TC of (3R) -3 _ [(third butoxycarbonyl) amine ] _4_ (2,4,5_tri-2phenyl) butanoic acid (95 mg) in a stirred solution of dichloromethane (5 ml), and the resulting mixture was stirred for 30 minutes. The hexahydro obtained in step D was added_3_ [4_ (Trifluoromethoxy) benzyl] -2'-1,4-diazepine-2-one hydrochloride (91 mg) & N-methylmorpholine (0.036 ml). The reaction mixture was at -20. 〇 Stir for 30 minutes and stir at ambient temperature for 2 hours, then evaporate. The residue was purified by preparative TLc (silicone, methyl 91662.doc-68- 200530202) / concentrated nitrogen oxide / dichloromethane 4.4: 0.1: 95.5), and the isomer was subsequently purified by HPLC (ChiralPAK AD, 7% Ethanol / hexane) was resolved to obtain the (R, R) -isomer which dissolves slowly. Step F: (3R) _M (3R) · 3 · amino group_4_ (2,4,5_trifluorophenyl) butyridyl group] Hexa-3--3- [4- (dimethoxymethoxy) benzyl group] _2H_1 , 4-Di-Vaphen-2-one (3R) -4 _ [(3R) _3-[(Third-butoxycarbonyl) amino] -4- (2,4,5-trifluorophenyl) butanyl ] Hexahydro-3- [4- (trifluoromethoxy) benzyl] _2H-1,4-di-p-heptane_2 is the same as that in 1M hydrogen in 4M gas and 2 · After 5 hours it was evaporated to obtain the desired product. LC / MS 504.2 (Μ + 1) 〇 Example 5

F

(3R) _4 _ [(3R) _3_amino_4_ (2,4,5_trifluorophenyl) butylfluorenyl] "Third butyl /, hydrogen-3 -methyl-2H-1,4-diP Acetyl ketone hydrochloride step A: N- (Third-butyl) yang-cyanoethyl) _2_oxopropionamine benzotriazole (2.4 g, 20 mmol) and thionyl chloride (15 ml) bis. The solution from the drop of the solution of Jiayuan (10 liters) to dichloromethane (10 ml) of propionate was dissolved and the mixture was stirred for 10 minutes. The precipitate formed was filtered and dichloromethane; Second wash. Test the magnesium sulfate treatment with Yi Erqie ^ milli ⑽ third butylamino) acetic acid solution. The reaction mixture: and gasification water treatment ^ ethyl acetate material. # 机 层 以 agger 91662.doc -69- 200530202 Sodium acid was dehydrated, filtered, evaporated and purified by BiQtage⑧ flash chromatography (e.g., ethyl acetate / hexanes 1: 1) to obtain an oily product. 2.74 (t? J = 7.4 Hz, it NMR (400 MHz, CDC13) δ 1.49 (s, 9H), 2.45 (s, 3H) 2Η), 3.6 (broad, 2Η). Step B: I. Third butyl hexahydro-3-methyl-2H_M di N- (Third-butyl) _N_ (2_Aminoethyl) _2_oxofluorenamine (440 mg) and oxygen Platinum (60 mg) was suspended in chloroform (03 ml) in ethanol (40 ml) and mixed in a Parr shaker under 40 psi hydrogen for "hours. The mixture was filtered, the catalyst was washed with methanol / dichloromethane (10:90) and the combined filtrates were evaporated; Purification by Biotage® flash chromatography (silica gel, 5-10% methanol / methane) gave the desired product.

H NMR (400 MHz, CDC13) δ 1.23 (d, J = 6.6, 3H), 1.43 (s, 9H), 1.5 (m, 1H), 1 · 7 (m, 1H), 2 · 9 (m, 1H ), 3.2 (m, 1H), 3.4 (m, 1H), 3.6 (m, 2H), LC / MS 185.2 (M + 1). Step C: (3R) -4 _ [(3R) _3-Amino_4_ (2,4,5-trifluorophenyl) butylfluorenyl] -1-tert-butyl-hexahydro_3_methyl_2H -1,4 · Diazepine-2-2-fluorene from (3R) -3-[(third butoxycarbonyl) amino] _4_ (2,4,5_trifluorophenyl) butanoic acid and 1- Second butyl-hexahydro-3_methyl_2,1,4-diazepine-2-one was prepared by the method described in Example 3, steps C and D, to the title compound. lc / ms 400 · 1 (M + 1). Example 6

91662.doc 200530202 4-[(3R) -3-aminobenzyl (24,5_trifluorophenyl) butylfluorenyl] _2H-1,4-diazepinone hydrochloride Step name A · Hexam-5 -Methyl-2H-1U Yaheptane was titled from crotononitrile to prepare a compound substantially following the procedures of steps A and B of Example 2. Steps are called B ·· 4_ [called 3_amino o-, ^ trifluorophenyl) butyryl] hexamine " 5-methyl-2H-1,4-di-p-heptane_2-fluorene from (3R) -3-[(Third butoxycarbonyl) amino] __ 4_ (2,4,5_trifluorophenyl) butyric acid hexahydro-5-methyl-yl 2-methylheptanine by Example 3 Step c and The title compound was prepared by the method described in Soil d. LC / MS 344.1 (M + 1). Example 7

(3R) _4-[(3R) -3-Amino-M2,4,5_trifluorophenyl) butylfluorenyl] hexahydro_3 _ [(1_oxy ionsulfonyl-2-yl) methyl 1,4_Diazepine_2one trixiangacetate step A: (3R) -4-[(3R) -3 _ [(third butoxycarbonyl) amino] _4_ (2,4,5 · tri Fluorophenyl) butyridinyl] hexahydroxanylpyridin-2-yl) methyl] -2H-1,4-diazepine-2-one Basically following the procedure described in Example 4 steps A to E . 91662.doc -71- 200530202

Step B ··· (3R) -4 _ [(3R) -3-Amino-4A2,4,5_trifluorophenyl) butylfluorenyl I hexahydro-3 _ [(1-oxopyridine Iyl) methyl ] Jjjd, 4 · Diazepine-2_one trifluoroacetate in (3R) -4-[(3R) -3-[(third butoxycarbonyl) amino] -4- (2,4, 5-trifluorophenyl) butylfluorenyl] hexahydro-3-[(l-oxopyridin_2_yl) methyl] _2H-1,4-diazepine-2_one (20 mg, 0.038 mmol) Ear) in methylene chloride (2.5 ml), mCPBA (28 mg, 0.096 mmol) was added at 0 C and the reaction mixture was stirred at ambient temperature overnight. The solution was treated with a saturated aqueous sodium bicarbonate solution and taken up with dichloromethane f. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (silicone, 11:89 ammonia in methanol / dichloromethane) to obtain N-BOC-protected batch sigma N-oxygen ions. Protect it with Sangas Ethyl-Dichloromethane (1: 1) at ambient temperature! Hours followed by concentration to obtain the desired product. MS 437.2 (M + 1). Example 8

(3R) _4 _ [(3R) _3_amino_4_ (2,4,5 · trifluorophenyl) butyridinyl] hexaoxypyridine-3-yl) methyl] diazepine triacetate basic The title compound was prepared following the procedure described in Example 7. 437.2 (Μ + 1) 〇 91662.doc -72- 200530202 Example 9

(3R) _4 _ [(3R) -3_amino_4_ (2,4,5-trifluorophenyl) butylfluorenyl] hexahydro • 3- (1II_pyrazole_1_ylmethyl) _2H-1, 4_Diazepine_2_one trifluoroacetate Step A: 4 Di [(benzyloxy) methyl] hexahydro · 3-oxo-1H_1,4-diazepine-1_carboxylic acid third Butyl vinegar was prepared from hexahydro-3-oxo-1H-M-diazepine tricarboxylic acid third butyl ester (Example 2 step B) and benzyl chloromethyl ether. The title compound was prepared essentially following the method described in Example 2 step c . Step B: 4 _ [(benzyloxy) f group] hexagon-2 · methylene-3-oxo-1H_1,4_diazepine-1-carboxylic acid third butyl ester [[benzyloxy Group) methyl] hexahydro-3-oxo-azepine 4-methylformyl second butyl ester and benzyl chloromethyl ether Basically following the procedure described in step 3 of Example 3 to prepare the title compound. Step C: 4-[(Benzyloxy) methyl] hexahydro-2- (1Η-pyrazol-1-ylmethyl) _3_oxo-1H-1,4-diazepine-carboxylic acid tert-butyl The ester was added to 10 ml of DMF in ° bizole (258 mg, 3.78 mmol), and sodium hydride (60%, 91 mg) was added at 0 ° C. The resulting mixture was stirred for 30 minutes and the product from Step B (65 5.4 g, 1.89 mmol) was added. The reaction was taught at ambient temperature and quenched by the addition of water. The aqueous mixture was extracted with three portions of ethyl acetate 91662.doc -73- 200530202. The combined organic phases were concentrated. Purification by flash chromatography (silica gel, 40-80% ethyl acetate / hexanes gradient) on a Biotage® device gave the title compound. Step D: 3- (lH-pyrazolylmethylperhydrodiheptain-2-one) The product of step C is treated with acetic acid. The reaction is stirred at ambient temperature for 7 days. The residue is left in toluene. The mixture was heated under reflux for 3 hours. The title compound was obtained by flash chromatography (silica gel, 5-15% methanol / ammonium hydroxide in dichloromethane) on a Biotage® device to obtain the title compound. Step name E · (3R ) _4-[(3R) · 3 · amino-4- (2,4,5-trifluorophenyl) butyryl] $ Hydrogen_3_ (111_pyrazole_1_ylmethyl MΗ), buckle Diazepine-2-ming trifluoroacetate from step D and (3R) _3 _ [(third butoxycarbonyl) amino] -4- (2,4,5-trifluorophenyl) butanoic acid The title compound was prepared essentially following the coupling method described in step e of Example 4. Purification by preparative TLC (stone gum, 1: 9 ethanol / dichloromethane) gave the N-BOC product as a mixture of diastereomers. Individual diastereomers were obtained by HPLC (chiralcell 0J column, 7% ethanol / hexane). Deprotection was performed with 1: 1 trifluoroacetic acid / dichloromethane at ambient temperature for 1 hour and then concentrated to obtain the individual diastereomers of the title compound. Enantiomers. MS 410.2 (M + 1). Basically follows Example 1- 9 Follow the procedure described in the preparation to prepare the compounds of Table 2. Table 2 5

91662.doc -74- 200530202

Example r! R! Rl MS fM + 1) 10 2-F, 5-F Me H 326,1 11 2-F, 4-F, 5-F CH2-cPr H 384.1 12 2-F, 4-F, 5-F Me Me 358.1 13 2-F, 5-F Me Et 354.1 14 2-F, 4-F, 5-F Me cPr 384.3 15 2-F, 5-F Me CH2C〇2Me 398.1 16 2-F, 4-F, 5-F Me CH2CH2〇H 388.1 17 2-F, 4-F, 5-F Me CH2CH2OCH2 c6h5 478.2 18 —2-F, 4-F, 5-F Et Me 372.2 19 2-F, 5 -F Et Me 354.1 20 2-F, 4-F, 5-F ch2〇h Me 374.0 21 2-F CH2Ph Me 398.2 22 3-F, 4-F CH2Ph Me 416.2 23 2-F, 4-F, 5 -F CH2〇CH2Ph Me 464.2 24 2-F, 4-F, 5-F Et H 358.1 25 2-F, 4-F, 5-F CH2Ph H 420.1 26 3-F, 4-F CH2Ph H 402.1 27 · 2-F, 5-F CH2 (4-〇CFr Ph) H 486.1 28 2-F, 4-F, 5-F CH2 (3-OCF3- Ph) H 504.2 29 2-F, 4-F, 5- F CH2CH (CH3) 2 Me 400.2 30 2-F, 4 ~ F, 5-F CH2 (3-CF3,5- CFrPh) H 556.2 31 2-F, 5-FHH 312.2 32 2-F, 4-F, 5-F CH2 (2-CF3-Ph) H 488.1 33 2-F, 4-F, 5-F CH2 (2-C1-Ph) H 454.0 91662.doc -75- 200530202 34 2-F, 4-F , 5-F CH2 (2-CH3- Ph) H 434.1 35 2-F, 4-F, 5-F CH2 (2-CH3,5- CH3-Ph) H 448.2 36 2-F, 4-F, 5 -F Me CHMe2 386.2 37 2-F, 4-F, 5-F CH2 (2-Ph- Ph) H 496.3 38 2-F, 4-F, 5-F CH2 (2-F, 5-F- Ph) H '456.1 39 2-F, 4-F, 5-F CH2 (2-F-Ph ) H 438.1 40 2-F, 4-F, 5-F Me CH2CF3 426.1 41 2-F, 4-F, 5 «F CH2 (2-F, 3-F- Ph) H 456.2 42 —2-F, 4-F, 5-F CH2 (3-pyridyl) H 421.1 43 2-F, 4-F, 5-F CH2 (2-F-Ph) CH2CH2CH3 480.2 44 2-F, 4-F, 5-F CH2 (4-pyridyI) H 421.1 45 2-F, 4-F, 5-F CH2 (2-F-Ph) Me 452.2 46 2-F, 4-F, 5-F CH2 (2-pyridyl) H 421.2 47 2-F, 4-F, 5-F CH2 (2-F, 6-F- Ph) H 456.3 48 2-F, 4-F, 5-F CH2CF3 H 412.3

Examples of pharmaceutical formulations. As for specific specific examples of oral Bile compositions, 100 mg of the strong bonding agent is composed of 100 mg of any compound of the present invention, 268 mg of microcrystalline cellulose, 20 mg of cross-linked methylcellulose sodium, and 4 mg of magnesium stearate. Blend first. Active ingredients, microcrystalline cellulose and croscarmellose sodium. The mixture is then lubricated with magnesium stearate and compressed into a lozenge. Although the present invention has been described and illustrated with reference to certain specific examples thereof, those skilled in the art will understand that procedures and strategies can be used for various applications, changes, modifications, substitutions, deletions or additions without departing from the spirit and scope of the invention. . 91662.doc -76- 200530202 For example, an effective dose other than the specific doses described herein can be applied as a result of changes in the response of a mammal to be treated with a compound of the present invention. The specific pharmacological response observed can vary depending on and depends on the particular active compound selected or the presence or absence of a pharmaceutical carrier, the type of formulation used and the mode of administration, and this expected change or result difference is intended to be within the objectives of the invention and Within practice. Therefore, the present invention is defined by the following patent application scope, and this patent application scope is interpreted in a reasonably widest manner.

91662.doc -77-

Claims (1)

200530202 X. Patent application park: 1. A compound of formula I Or a pharmaceutically acceptable salt thereof; wherein each n is independently 0, 1 or 2; Ar is phenyl substituted with 1 to 5 R3 substituents; R1 is selected from the group consisting of: chlorine; alkyl, Wherein the alkyl group is unsubstituted or substituted with 5 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, Cw alkoxy, carboxyl, alkoxycarbonyl and phenyl-CN3 alkoxy, wherein alkoxy The United States is unsubstituted or substituted with 1 to 5 i primes; (CH2) n-aryl, wherein the aryl is unsubstituted or substituted with 5 to 5 independently selected from the group consisting of functional elements, CN, hydroxyl, R2, or2, NHS. 2R2, Nr2s〇2r2, So2R, Co2H & C1 · 6 alkoxycarbonyl substituent; (CH2) n-heteroaryl, wherein heteroaryl is unsubstituted or independently selected Substituted by a substituent of a hydroxyl group, a prime element, a Cl.6 alkyl group, and a Cl-6 alkoxy group, wherein the alkyl group and the alkoxy group are unsubstituted or substituted with 5 to 5 halogens; Wherein the heterocyclic group is unsubstituted or substituted with 1 to 3 substituents independently selected from oxo, hydroxyl, halogen, Cw alkyl, and Ci6 alkoxy 91662.doc 200530202, wherein the alkyl group and alkoxy group Substituted or substituted with 1 to 5 halogens; (CH2) n-C3.6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 3 to 3 independently selected from halogen, hydroxyl, Cl-6 alkyl, and O " Substituted by alkoxy, wherein the alkyl and alkoxy are unsubstituted or substituted with 5 to 5 halogens; and any methylene (CH2) carbon atom in W is unsubstituted or independently selected Prestige, hydroxy, and unsubstituted or substituted with 2 to 5 halogen substituted 4 substituents; each R3 is independently selected from the group consisting of: hydrogen; halogen; cyano; hydroxyl; C 1 The group 'is unsubstituted and substituted with 5 to 5 i; C 1-6 oxo group is unsubstituted, substituted to 5? / JLi 1 >. Substituted or substituted with 1 to 5 halogens; Wei group; Alkoxyweenyl; Amine; NHR2; NR2R2; NHS02R2; nr2so2r2; NHCOR2; 91662.doc 200530202 nr2cor2; nhco2r2; nr2co2r2; so2r2; so2nh2; so2nhr2; and each of which is independent of 2 Substituted or substituted by 5 to 5 substituents independently selected from halogen, CO2H and Ci-6 alkoxycarbonyl R4 and R5 are independently selected from the group consisting of: hydrogen; cyano; C 1-6 alkoxyl; to 5 independently selected from halogen, Cl-6 alkoxycarbonyl and phenyl among which Unsubstituted C 1-10 alkyl, which is unsubstituted or substituted with a substituent of 1 hydroxy, Cw alkoxy, carboxyl, -C! · 3 alkoxy, or 1 to 5 halogens; (CH2) n-aryl, wherein the aryl is unsubstituted or substituted with a substituent independently selected from the group consisting of _ ′ ′ ′ ′ ′ and alkoxy, wherein the alkynyl group and the alkoxyl group are unsubstituted; (CH2) The n-heteroaryl group is selected from the group wherein the heteroaryl group is unsubstituted or substituted! to 3 independent groups * Cl_6 alkyl group and Cl.6 alkyloxy substituent 91662.doc 200530202 substituted 'wherein the alkyl group and alkyl group Oxygen is unsubstituted or substituted with 5 to 5 halogens; (CH2) n-heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with 3 to 3 independently selected from the group consisting of oxo, hydrazine, hydrogen, and Ci-6 And alkyl substituents, wherein the alkyl and alkyl groups are unsubstituted or substituted with 1 to 5 halogens; (CH2) n-C34 alkyl, where the cycloalkyl group is unsubstituted or substituted independent Since halogen, Peru. Alkyl and one-substituent substituents, in which the alkyl and hydroxy groups are unsubstituted or substituted with 1 to 5 halogens; (CHACONW 'where ... and R7 are independently selected from hydrogen, tetrasialyl, thiazolyl, (CH2) n-phenyl, (CH2) n_C36 cycloalkyl, and alk-6 alkyl group, in which the alkyl group is unsubstituted or substituted with 5 to 5 halogen and phenyl and cycloalkyl Unsubstituted or substituted with i to 5 substituents independently selected from halogen, hydroxy, Ci-6 alkyl and 6 alkoxy, wherein the alkyl and alkoxy are unsubstituted or substituted with 1 to 5 primes; Or, R, R and R together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from the group consisting of orallydin, pyrrolidine, piperidine, piperin, and morpholine; and wherein the heterocyclic ring is unsubstituted Or substituted with 5 to 5 substituents independently selected from halide, anthryl, alkyl and Cl_6 alkoxy, wherein the alkyl and alkoxy are unsubstituted or substituted with! To 5 halogens; and wherein M Any fluorenylene (CH2) carbon atom in 戋 R is unsubstituted or substituted with 至 to 2 unique L selected from halogen, hydroxyl and unsubstituted or substituted with 取代 to 5 halogen q * 91662.doc 200530202 Substituent for alkynyl; and R and R9 are each independently hydrogen or Cu alkyl. 2. If the compound in the scope of application for item 1 is a compound of formula la ... The carbon atom in which k § has * has an r configuration, and Ar, Ri, R4, R, R8, and R9 are as defined in the scope of patent application. 3. The compound according to item 1 of the scope of patent application, wherein R3 is selected from the group consisting of: hydrogen; ci-6 alkyl group, which is unsubstituted or substituted with 5 to 5 carbon atoms; Ci-6 carbonoxy group _ Is unsubstituted or substituted with 1 to 5 halogens. 4. The compound according to item 3 of the scope of patent application, wherein R3 is selected from the group consisting of hydrogen, fluorine, gas / odor, difluoromethyl and fluorenyl. 5. The compound according to item 4 of the patent application, wherein R3 is selected from hydrogen, fluorine or chlorine. 6. The compound according to item 1 of the scope of patent application, wherein R1 is selected from the group consisting of: chlorine; 91662.doc 200530202 q-6 alkyl, wherein the alkyl group is unsubstituted or independently selected from 卣Substituted by the substituents of sulfonium, hydroxy, Cl-6 alkoxy, fluorenyl, c "alkoxycarbonyl, and phenyl-Cw alkoxy, wherein the xyloxy group is unsubstituted or substituted with 1 to 5 oxins; (CH2 ) n-C3-6 ^ alkyl, wherein the cycloalkyl group is unsubstituted, and is selected from the group consisting of -prime, substituted by a radical and a aryl group, wherein the alkyl and alkoxy groups are unsubstituted or 5 halogen substitutions; and any of R1—he methylene (CH2) carbon atom is unsubstituted or substituted with 2 to 2 independently selected from the group consisting of hydrogen, unsubstituted or alkyl substituted with 1 to 5 halogens Substituent substitution. 7. The compound according to item 6 of the patent application, wherein Ri is selected from the group consisting of: hydrogen; C 1-4 alkyl; 2,2,2-trifluoroethyl; methoxy Carbonylmethyl; carboxyfluorenyl; hydroxyethyl; benzyloxyfluorenyl; fluorenylethyl, and cyclopropyl. 8. The compound according to item 7 of the patent application, wherein R 1 is selected from the group consisting of hydrogen, methyl, third butyl, and cyclopropyl. 91662.doc 200530202 9. If the scope of the patent application is the first one, R4 & R5 is selected from A group consisting of: nitrogen; a Cl-10 ^ group, which is unsubstituted or independently selected from 1 to 5 and is independently selected from the group consisting of oxin, < Ci 6 alkoxy and phenyl C1-3 alkoxy is substituted by substituents, wherein the alkoxy group is unsubstituted or substituted with 1 to 5 atoms; (CH2) n aryl, wherein the aryl group is unsubstituted or independently selected from 1 to $ Processin, hydroxyl, Cl · 6 alkyl and Cl · 6 alkoxy substituents, wherein alkyl and alkoxy groups are unsubstituted or substituted with 5 to 5 halides; (CHA-heteroaryl, where Heteroaryl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of hydroxyl, hydrogen, Cl.6 alkyl, and Ci-6 alkoxy, wherein the alkyl and alkoxy are unsubstituted or 5 halogen substitutions; (CH2) n • heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from oxo, hydroxyl, halogen, Cw alkyl, and Ci6 alkoxy , Where the Group and alkoxy group are unsubstituted or substituted with 1 to 5 i elements; (CH2) n-C3 · 6 cycloalkyl group, wherein cycloalkyl group is unsubstituted or independently selected from 1 to 3 halogen, , Cw alkynyl and Cl.6 alkoxy substituents' where the alkynyl and alkoxy are unsubstituted or substituted with 1 to $ halogens; where any methylene (CH2) carbon atom in R4 or R5 Unsubstituted or substituted by 1 to 2 91662.doc 200530202 Substituted by 1 to 5 halogens independently selected from the group consisting of prime, hydroxyl and unsubstituted or. !! -Substituted by 4 substituents. Among them, R4 and R5 are independently selected from the group consisting of the following compounds such as the item 9 of the scope of the patent application: hydrogen; alkyl 'which is unsubstituted or independently selected from the group consisting of halide, hydroxyl, and Cw (CH2) n-aryl 'is substituted by substituents of oxy, alkynyl, Ci6alkyloxy, and phenylhydrazone3alkyloxy. Wherein the aryl group is unsubstituted or substituted by two substituents independently selected from the group consisting of halogen, via a radical, a radical and Cl.6 oxygen, wherein the alkyl and alkoxy radicals are unsubstituted or substituted by 1 to 5 (CH2) n · heteroaryl 'in which the heteroaryl group is unsubstituted or is independently selected from the group consisting of a mesityl group, an i group, and a Cl group. Substituted by a substituent of an alkoxy group, wherein the alkynyl group and the alkoxy group are unsubstituted or substituted with two halogens; (CH2) n-C3 · 6 cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted by 1 to 3 Each independently selected from the group consisting of a hormone, a hydroxyl group, a Cl.6 alkyl group, and a Ci6 alkoxy group, wherein the alkyl group and the alkoxy group are unsubstituted or substituted with 5 to 5 halogens; wherein any of R4 or R5 The methylene (CH2) carbon atom is unsubstituted or substituted with []] independently selected from the group consisting of halides, cyclic groups, and unsubstituted or… groups: substituted Cw alkyl groups. 91662.doc 200530202 11. The compound according to item 10 of the patent application range, wherein R4 and R5 are independently selected from the group consisting of: hydrogen; ch3; CH2CH3; CH2CH (CH3) 2; CH2-cyclopropyl; ch2-cyclohexyl; CH2〇CH2Ph; CH2OH; CH2Ph; CH2 (3-OCF3-Ph); CH2 (4-OCF3-Ph); CH2 (3-CF3,5-CF3-Ph); CH2 (2-CF3 -Ph); CH2 (2-Cl-Ph); CH2 (2-Me-Ph); CH2 (2_Me, 5-Me-Ph); CH2 (2-Ph-Ph); CH2 (2-F, 5 -F-Ph); CH2 (2-F-Ph); CH2 (2-F? 3-F-Ph); CH2 (2-pyridyl); CH2 (3-pyridyl); 91662.doc 200530202 CH2 ( 4-pyridinyl); CH2 (1-oxopyridin-2-yl); CH2 (1-oxopyridin-3-yl); CH2 (lH-n-pyrazol-1-yl); CH2 (2 -F, 6-F-Ph); and CH2CF3. 12. The compound as claimed in claim ^, wherein R5 is hydrogen. 13. The compound according to item 1 of the patent application range, wherein R8 and R9 are independently selected from hydrogen and methyl. 14. The compound according to item 13 of the application, wherein R8 and R9 are hydrogen. 15. The compound according to item i in the scope of patent application, wherein "is selected from the group consisting of: C 1-4 alkyl; 2,2,2-tridecyl ethyl; fluorenyloxycarbonyl; carboxymethyl Hydroxyethyl; benzyloxymethyl; benzyloxyethyl; and bad propyl; R3 is hydrogen, gas or fluorine; R4 is selected from the group consisting of: hydrogen; 91662.doc 200530202 ch3; ch2ch3; CH2CH (CH3) 2; ch2-cyclopropyl; CH2_cyclohexyl; CH2OCH2Ph; CH2〇H; CH2Ph; CH2 (3-OCF3-Ph); CH2 (4-OCF3-Ph); CH2 (3-CF3 5-CF3-Ph); CH2 (2-CF3-Ph); CH2 (2-Cl-Ph); CH2 (2-Me-Ph); CH2 (2-Me, 5-Me-Ph); CH2 ( 2-Ph-Ph); CH2 (2-F? 5-F-Ph); CH2 (2-F-Ph); CH2 (2-F, 3-F-Ph); CH2 (2-pyridyl); CH2 ( 3-pyridyl); CH2 (4-pyridyl); CH2 (1-oxopyridin-2-yl); CH2 (1-oxopyridin-3-yl); 91662.doc -11-200530202 CH2 (1H-pyrazol-1-yl); CH2 (2-F, 6-F-Ph); and CH2CF3; and R8 and R9 are hydrogen. 16. The compound of item 15 in the scope of patent application, wherein R5 is hydrogen 17. If the compound in the scope of patent application No. 15 is applied, Is selected from the group consisting of the following: 91662.doc -12- 200530202 F Or a pharmaceutically acceptable salt thereof. 18. The compound according to item 15 of the scope of patent application, which is selected from the group consisting of the following structural formula lb: lb 91662.doc -13- 200530202 r! R! Rl 2-F, 5-F Me H 2-F, 4-F, 5-F CH2-cPr H 2-F, 4-F, 5-F Me Me 2 -F, 5-F Me Et 2-F, 4-F, 5-F Me cPr 2-F, 5-F Me CH2C02Me 2-F, 4-F, 5-F Me CH2CH2〇H 2-F, 4 -F, 5-F Me CH2CH2OCH2 c6h5 2-F, 4-F, 5-F Et Me 2-F, 5-F Et Me 2-F, 4-F, 5-F ch2〇h Me 2-F CH2Ph Me 3-F, 4-F CH2Ph Me 2-F, 4-F, 5-F CH2〇CH2Ph Me 2-F, 4-F, 5-F Et H 2-F, 4-F, 5-F CH2Ph H 3-F, 4-F CH2Ph H 2-F, 5-F CH2 (4-OCF3- Ph) H 91662.doc 14- 200530202 2-F, 4-F, 5-F CH2 (3-OCF3- Ph ) H 2-F, 4-F, 5-F CH2CH (CH3) 2 Me 2-F, 4-F, 5-F CH2 (3-CF3,5- CF3-Ph) H 2-F, 5-FHH 2-F, 4-F, 5-F CH2 (2-CF3-Ph) H 2-F, 4-F, 5-F CH2 (2-Cl-Ph) H 2-F, 4-F, 5- F CH2 (2-CH3- Ph) H 2-F, 4-F, 5-F CH2 (2-CH3,5- H CH3-Ph) 2-F, 4-F, 5-F Me CHMe2 2-F , 4-F, 5-F CH2 (2-Ph-Ph) H 2-F, 4 «F, 5-F CH2 (2-F, 5-F- Ph) H 2-F, 4-F, 5 -F CH2 (2-F-Ph) H 2-F, 4-F, 5-F Me CH2CF3 2-F, 4-F, 5-F CH2 (2-F, 3-F- Ph) H 2- F, 4-F, 5-F CH2 (3-pyridyl) H 2-F, 4-F, 5-F CH2 (2-F-Ph) CH2CH2CH3 2-F, 4-F, 5-F CH2 (4 -pyridyl) H 2-F, 4-F 5-F CH2 (2-F-Ph) Me 2-F, 4-F, 5-F CH2 (2-pyridyl) H 2-F, 4-F, 5-F CH2 (2-F, 6-F -Ph) H 2-F, 4-F, 5-F CH2CF3 H or a pharmaceutically acceptable salt thereof. 91662.doc -15- 200530202 19 20. • A medical music composition, including the compound in the scope of patent application and a pharmaceutically acceptable carrier. For example, the pharmaceutical composition under the scope of patent application No. 19, which further includes one or more other active ingredients far from the following groups: (a) a second dipeptidyl peptidase IV (DP-IV) inhibitor (B) an insulin sensitizer selected from the group consisting of pRARy agonist, PRARa / γ dual agonist, pAPRa agonist, biguanide, and protein tyrosine phosphatase-1B inhibitor; (c) Insulin or insulin-like; (d) Sulfonylurea or other insulin secretagogues; (e) A-glycosidase inhibitors; (f) Glucagon receptor antagonists; (g) GLP-1, GLP -1 mimetic or GLP-1 receptor agonist; (h) GIP, GIP mimetic or GIP receptor agonist; (i) PACAP, PACAP mimetic or PACAP receptor agonist; (j) cholesterol lowering agent, Such as ⑴HMG-CoA reductase inhibitors; ⑴) sequestrants; (iii) final test alcohol, final test acid or salt thereof; (iv) ppA inverse agonist; (v) PPARa / Y dual agonist; (Vi) cholesterol absorption inhibitors; (vii) fluorenyl CoA: cholesterol phosphotransferase inhibitors; and (viii) phosphonium oxidants; (k) PPARS agonists; (l) anti-obesity compounds (M) ileal bile acid transmission inhibitors; (η) anti-inflammatory drugs; and 91662.doc -16- 200530202 (〇) 4 blood pressure agents. 28 29. 30. The pharmaceutical composition according to the scope of patent application, wherein the metformin. -A material such as the compound of the scope of application for patent! It is a medicine for treating mammals selected from the group consisting of hyperglycemia, type 2 diabetes: conditions of lipid disorders. ^ As described in item 29 of the scope of patent application, W dysfunction is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceride & cholesterol, low-HDL and high LDL . ... 91662.doc 17- 200530202 VII. Designated representative map: (1) The designated representative map of this case is: (none) (II) The component symbols of this representative map are briefly explained: 8. If there is a chemical formula in this case, please disclose the best display of the invention Chemical formula of characteristics: 91662.doc